PT1478629E - N-aryl-2-oxazolidinone-5-carboxamides and their derivatives and their use as antibacterials - Google Patents

Description

1-N-ARYL-2-OXAZOLIDINONE-5-CARBOXAMIDES AND THEIR DERIVATIVES AND THEIR USE AS ANTIBACTERIALS " The present invention relates to novel N-Aryl-2-oxazolidinone-5-carboxamides, their derivatives, and their preparations. These compounds possess potent antimicrobial activity.

BACKGROUND OF THE INVENTION

Oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens including gram-positive aerobic bacteria such as staphylococci and multiple resistance streptococci, anaerobic organisms such as bacteroids and clostridia species, and resistant organisms to acids such as Mycobacterium tuberculosis and Mycobacterium avium.

For a review of such antibacterial oxazolidone agents see Brickner SJ, Current Pharmaceutical Design, 1996, 2, 175-194. EP 0 697 404 A discloses substituted 1-phenyl-2-oxo-oxazolidine-5-carboxylic acid derivatives useful as adhesion receptor antagonists.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds of

formula I B-A-Jnhr.

O

I or a pharmaceutically acceptable salt thereof wherein: A represents a structure i, ii, or iii

C represents aryl or heteroaryl, wherein each of the aryl and heteroaryl are optionally substituted with 1-3 of R2; B is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, het and het substituted, or B and an R 2, if present, together with the phenyl carbon atoms to which B is R 2 and R 2 are attached, form a het, wherein het is optionally substituted het, provided that when C is phenyl optionally substituted with R2 then B does not represent

Q is independently selected from H, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, phenyl, benzyl, -OH, CF 3, CCI 3, -NR 3 R 3, -C 1 -C 6 alkylene-NR 3 R 3, C 1 -C 6 alkylene- ( CH2 phenyl) -NR3 R3, C1 -C6 alkylene- (CH2 benzyl) -NR3 R3, and

R1 is selected from H, -OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino, substituted alkyl, substituted alkoxy, and substituted alkenyl;

Each R 2 is independently selected from H, alkyl, amino, NO 2, -CN, halo, and substituted alkyl; and each R 3 is independently selected from H or C 1 -C 6 alkyl.

Embodiments of this aspect of the invention may include one or more of the following embodiments. 4 ΡΕ1478629

Each R2 is independently selected from H, F,

Cl, Br, CN, NH 2 O

N02, CF3, and CH3. The structure of A is

Hello

R1 is H -NH2, -OH, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, or C2-4 alkenyl, the alkyl, alkoxy and alkenyl each being optionally substituted with one or more halo, - OH, -CN. R 1 represents H -OH, -CH 2 -CH = CH 2, methyl, ethyl, propyl, -CH 2 -CH 2 F, -CH 2 -CH 2 OH, or methoxy. B represents het or het substituted such as morpholinyl, piperazinyl, pyridyl, thiomorpholinyl, 3,6-dihydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl, 3,6-dihydro-2'-pyranyl, tetrahydro-2H-pyranyl, azetidinyl, 5,6-dihydro-4H- [1,3,4] thiadiazinyl, 2,5-dihydro-1H-pyrrolyl, 3,4-dihydro-1 (2H) - pyridinyl, tetrahydropyridyl, 5,7-dihydro-6H-pyrrolo [3,4-b] pyridinyl, 2,3-dihydro-4H-1,4-thiazinyl, each of which is morpholinyl, piperazinyl, pyridyl, thiomorpholinyl, 3,6-dihydro-2 H -thiopyranyl, tetrahydro-2H-thiopyranyl, 3,6-dihydro-2 H -pyranyl, tetrahydro-2H-pyranyl, azetidinyl, 5,6- dihydro-4H- [1,3,4] thiadiazinyl, 2,5-dihydro-1H-pyrrolyl, 3,4-dihydro-1 (2H) -pyridinyl, tetrahydropyridyl, dihydro-6 H -pyrrolo [3,4-b] pyridinyl, 2,3-dihydro-4 H -1,4-thiazinyl optionally substituted with 1-4 groups selected from = O, alkyl, substituted alkyl, and halo. amino, substituted amino, -OH, = NOH, = C1-4alkyl, B is selected from ΡΕ1478629 5

6 ΡΕ1478629

• 8

GZS

N? or

One R2 represents hydrogen and the other R2 represents F. Both R2 substituents represent F. A R2 and B together form a het. R2 and B form -CO- (O) -N (Q50) -O-C (O) -N (Qso) -N (Qso) -HCQ50 -CH2-NQO-C-NQsq-C (O) -CH2 O -C (O) -CF 2 -O-, -NOS-C (O) -CH 2 -S-, -NO 2 O-C (O) -CF 2 -S-, -NOSso-C (S) -CH 2 - S-, -NQsq-C (O) -CH 2 -CH 2 -, -CH 2 -CH 2 -NO 5 -CH 2 -CH 2 -, or -CH 2 -NQ 50 -CH 2 -CH 2 -CH 2 -, where Q 50 represents H or C 1-4 alkyl optionally substituted with 1-3 of = 0, or -OH. Q 50 represents methyl, isopropyl, ethyl, formyl, acetyl, or -C (O) -CH 2 OH.

In another aspect, the invention provides compounds

of formula II

IX or a pharmaceutically acceptable salt thereof wherein: A represents a structure i, ii, or iii

O

7 ΡΕ1478629 B is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, het, and het substituted, or B and R2 together with the phenyl carbon atoms to which B and R2 are attached, form a het, with het being optionally a het substituted, provided that B does not represent

Q is independently selected from H, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, phenyl, benzyl, -OH, CF 3, CC 13, -NR 3 R 3, -C 1 -C 6 alkylene-NR 3 R 3, C 1 -C 6 alkylene- ( NR 3 R 3, C 1 -C 6 alkylene- (CH 2 benzyl) -NR 3 R 3, and

R1 is selected from H, -OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino, substituted alkyl, substituted alkoxy, and substituted alkenyl;

Each R 2 is independently selected from H, alkyl, amino, NO 2, -CN, halo, and substituted alkyl; ΡΕ1478629

from H

Each R 3 is independently selected or C 1 -C 6 alkyl. a compound

In another aspect the invention relates to the formula III

or a pharmaceutically acceptable salt thereof represents a structure i, ii, or iii

1 where: A

B represents the

B)

W

ΡΕ1478629 9

(L) a diazinyl group optionally substituted with X and Y, m) a triazinyl group optionally substituted with X and Y, n) a guinolinyl group optionally substituted with X and Y, (o) a guinoxalinyl group optionally substituted with X and Y , p) a naphthyridinyl group optionally substituted with X and Y,

q) r

s

ΡΕ1478629 11 Υ Ν u) Μ

aa) ΡΕ1478629 12

13 ΡΕ1478629

B and an R2 are taken together to form

ΡΕ1478629 14

A1 represents a) H-, or b) CH3; A2 represents

(a) H-, b) HO-, c) ch3-, d) ch3-, e) C1-C2 alkyl, CH3-C (O) -, (CH3-C (O) - (CH3-C (O) -CH 2 -, m Ο Ό, or

O-V n

0 'A1 and A2 taken together represent:

b) 0, or c) A 3 represents any 5-10 membered aryl or hetaryl ring, the het 1-4 heteroatoms selected from O, S, or N;

Bi represents a) -N = C (H) -C (H) = C (H) -, or b) -C (H) = N-C (H) = C (H) -; 16 ΡΕ1478629

Di is a) 0, b) S, or c) -N (R304) -; E represents a) NR 39, b) -s (= O) i, c) 0, or d) -s (= O) (= nr 315);

Fi is (a) 0, b) s, c) NH, d) N-OH, e) N-O-C4-4 alkyl, or f) N-OC (O) -C4-4 alkyl;

Ki represents a) 0, b) S, or c) -NR305-; M represents a) H, b) C4-8 alkyl, c) C3-8 cycloalkyl, d) - (CH2) m OR13, or e) - (CH2) h -NR21 R22;

Ti represents a) -O-, b) -NR3 06-17 ΡΕ1478629 c) -S-, or d) -SO2-; V represents a) 0, b) CH 2, or c) n r 87; W represents a) CH, or b) N;

W1 is a) -NH-, b) 0, or c) S; X represents a) H, b) -SH, h) -S (= O) R4, i) -C (O) = O) R7, j) -C (= O) R25, k) -C (= O) NR27 R28, D-C (-NR29) R25 rm) -C (R25) (R28) -OR13, (R 28) -O C (= O) R 13, O) -C (R 28) (OR 13) - (CH 2) h -NR 27 R 28, 18 ΡΕ 1478629 P) -NR 27 R 28, q) -N (R 27) ) R7, r) -N (R27) -S (= O) 1 R7, s) -C (O R14) (ORis) R28, t) -C (R25) (R16) one or more halos, OH,: at a position other than the alpha position, -S (= O) R17, NR27 R28, C2-5 alkenyl, C2-5 alkynyl, or C3-8 cycloalkyl; Y represents a) H, b) F, c) Cl, d) Br, e) C 1-3 alkyl f) NO 2; Ζ represents a) Ο, b) S, or c) NM;

Z 1 represents a) -CH 2 -, b) -CH (R 10 4) -CH 2 c) -C (O) -, or d) -CH 2 CH 2 CH 2 -; Z 2 represents a) -S (O) i-, b) -O-, d) c) -N (R07) -, or -S (= O) (= NR315); 19 ΡΕ1478629 Z3 represents a) -S (O) i-, < b) -O-, z4 is a) -s (= O) i-, b) -NR303-; z5 represents a) -o-, b) -NH-, c) -CH2 -, or d) -s (= O) i-; (c) S (= NR315) (z7 represents a) N, b) CR110, c) CR115, or d) CR116; Ζ8 represents a) 0, or b) S;

R1 represents a) H, b) -OH, with an optionally substituted C1-6 alkyl substituent or more halos, -OH, -CN, aryl, het, alkoxy, substituted aryl or substituted het; d) optionally substituted C1-6 alkoxy e) C1-6 alkoxy optionally substituted with aryl, het, substituted aryl or het substituted, f) -NH2, or g) substituted by one or more halo, -OH, -CN, aryl, het, substituted aryl or substituted het, C3-5 cycloalkyl; R 2 represents a) H, b) C 1-2 alkyl optionally substituted with one or more halos, c) -NH 2, d) -NO 2, e) -CN, or f) halo; R4 represents a) C1-4 alkyl optionally substituted with one or more halos, OH, CN, NR10 R11, or -CO2 R13, b) C2-4 alkenyl, C) -NR16 R18, d) -NHC (= O) R7, e) -NR20 C (= R5, R5, R5, R5, R5, R5, R5, R5, R5, R5, R5, R5, R5 and R6 taken together are the same or different and are - (CH2) k-; 21 ΡΕ1478629 R7 represents a) C1-4 alkyl optionally substituted with one or more halos;

Rio and Rn at each occurrence are the same or different and represent a) H, b) C4-4 alkyl, or c) C3-8 cycloalkyl; R13 represents a) H, or b) C4-4 alkyl; R14 and R15 at each occurrence are the same or different and represent a) C4-4 alkyl, or b) R14 and R15 taken together represent - (CH2) n -; R16 represents a) H, b) C4-4 alkyl, or c) C3-8 cycloalkyl; a) C4-4 alkyl, or b) C3-8 cycloalkyl; e) a) H, b) C4-4 alkyl, c) C2-4 alkenyl F d) C3-4 cycloalkyl and e) -OR13 or f) -NR21R22; 22 ΡΕ1478629 R20 represents a pharmaceutically acceptable cation, such as sodium, potassium, lithium, calcium or magnesium; R21 and R22 at each occurrence are the same or different and represent a) H, b) C1-4 alkyl, or c) R21 and R22 taken together represent - (CH2) m-; R25 represents a) H, b) C1-8 alkyl optionally substituted with one or more halos, C3-8 cycloalkyl, C1-4 alkyl substituted with one or more of -S (= O) R17, -OR13, or C (= 0) R13, NR27R28, or c) C2-5 alkenyl optionally substituted with -C (O) H, or CO2 R13; R26 represents a) R28r or b) -NR27N28; R27 and R28 at each occurrence are the same or different and represent a) H, b) C1-8 alkyl, c) C3-8 cycloalkyl, d) - (CH2) m OR13, e) (CH2) h NR2 R221 or f) R2 R 7 and R 8 taken together represent (CH 2) 2 (CH 2) 2 -, - (CH 2) h CH (COR 7) -, or - (CH 2) 2 N (CH 2) 2 (R 7); (A) -NR 27 R 28, b) -OR 27, or c) -NHC (= O) r 28; (A) H, or b) C4-4 alkyl optionally or more halos, OH, C1-4 alkoxy, CN, SH -N (R3i) 2, or -S (O) 4R3i; R31 represents a) C4-4alkyl, b) -C (O) C4-4alkyl, c) -C (O) O-C4-4alkyl, d) -C (O) NH2, e) -C (O) NH-C4-4alkyl, or f) -S02 C4-4 alkyl; R38 represents a) H, b) C4-6 alkyl, c) - (CH2) q -aryl, or d) halo; R39 represents H, b) C4-6 alkyl optionally OR plus OH, halo, or -CN, c) - (CH2) q -aryl, d) -C02 R4o, e) -COR44, f) -C (= O) - ( CH2) q C (= O) r40, g) -S (= O) 2 -C4-6 alkyl, h) -S (= O) 2- (CH2) q -aryl, or i) - (C = O) Het; substituted C1-6 alkyl substituted with one or more OH, halo, or -CN, c) - (CH 2) q - aryl, or d) - (ch2) q -OR42; R 4i represents a C 1-6 alkyl optionally substituted with one or more OH, halo, -O P (O) (OH) 2, -O P (OH) 2, or -CN, b) - (CH 2) q -aryl, or c) - (CH 2) q -OR 42; R42 represents a) H, b) C1-6 alkyl, c) - (CH2) q -aryl, or d) -C (= O) -C1-6 alkyl; R49 and R50 at each occurrence are the same or different and represent a) H, b) C1-4 alkyl, c) C5-6 cycloalkyl, or d) R49 and R50 taken together with the nitrogen atom represent a saturated 5-6 membered heterocyclic moiety which optionally has an additional heteroatom selected from the group consisting of S, N, and O, and may in turn be optionally substituted with, on the additional nitrogen atom, C1-3 alkyl or C1-3 acyl; (E) formyl, f) cf3, g) -NO2, h) C1-6 alkoxy, i) C1-6 alkoxycarbonyl, j) C1-6 alkoxycarbonyl, (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 1 -C 6) alkyl optionally having C 1 -C 5 alkoxy, C 1 -C 5 acyl, or - NR 49 R 50, m) phenyl, n) -C (= O) NR 52 R 53, NR 49 R 50, P) -N (R 52) (-so 2 R 54), q) -SO 2 -NR 52 R 53, or r) -s (= O) R 54; R52 and R53 at each occurrence are a) H, b) C1-6 alkyl, or c) phenyl; and R74 at each occurrence are the same or different and represent a) H, b) carboxyl, c) halo, d) -CN, e) mercapto, f) formyl, g) CF3, h) -NO2, i) C1-6 alkoxy, j) C1-6 alkoxycarbonyl, k) C1-6 alkylthio, i) C1-6 acyl, m) -NR78 R79, n) optionally substituted C1-6 alkyl (OCH 2 CH 3), or -O-phenyl- [para-NHC (= O) -CH 2 CH 3, CH3], o) C2-8 alkenyl-phenyl optionally substituted with R5i, p) phenyl optionally substituted with R5i, or q) a saturated or unsaturated, 5-6 membered heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with R 5i; R78 and R79 at each occurrence are the same or different and represent a) H, b) C1-4 alkyl, c) phenyl, or d) R78 and R79 taken together with the nitrogen atom represent a saturated heterocyclic moiety of 5,6 membered ring optionally having an additional heteroatom selected from the group consisting of S, N, and O, and may be in turn optionally substituted with, on the additional nitrogen atom, C1-3 alkyl or C1-3 acyl -3;

R 2 represents a) H, b) formyl, c) carboxyl, d) C 1-6 alkoxycarbonyl, e) C 1-6 alkyl, C 2-8 alkenyl, wherein the substituents (e) and (f) may be optionally substituted C 1-6 -alkyl or C 1-6 -alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF 3, -NO 2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 acyl, C 1-6 alkylthio, or C 1-6 alkoxycarbonyl; h) -NRg Rg 2, i) -OR 90, j) -S (= O) R 9a, or k) -so 2 -N (R 92) (R 93);

Rsi and R82 at each occurrence are the same or different and represent 28 ΡΕ1478629 a) Η b) C3-6 cycloalkyl, c) phenyl, d) C1-6 acyl and e) C1-6 alkyl optionally substituted with OH, C1-6 alkoxy which may be substituted with OH, a 5-6 membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF 3, halo, -NO 2, C 1-4 alkoxy, NR.83R.84 r or f)

O

or

R 3 and R 4 at each occurrence are the same or different and represent a) H, or b) C 1-4 alkyl; R85 represents a) OH b) C1-4 alkoxy, or c) -NR88R89A 29 ΡΕ1478629

R 6 represents a) H, or b) C 1-7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazolyl, methylthio, amino, phenyl optionally substituted with OH, -C (= O) -NH 2, -C02 H, or -C = NH) -NH 2;

R7 represents a) H, b) phenyl, or c) C1-6 alkyl optionally substituted by OH; R88 and R89 at each occurrence are identical or different and represent a) H, b) C 1-5 alkyl c) C 3-6 cycloalkyl, or d) phenyl; R 90 represents a) C 1-8 alkyl optionally substituted with C 1-6 alkoxy or C 1-6 hydroxy, C 3-6 cycloalkyl, an optionally benzo-condensed, 6-membered aromatic heterocyclic moiety having one to three nitrogen atoms, which may, be substituted with one or two -NO2, CF3, halo, -CN, OH, C1-6 alkyl, C1-6 alkoxy, or C 1-5 acyl; b) (c) phenyl, or (d) pyridyl; (A) C 1-6 alkyl, b) C 2-6 alkenyl wherein the substituents (a) and (b) may optionally be substituted with C 1-6 alkoxycarbonyl, or an aromatic heterocyclic moiety of 5,6, 7-membered ring having one to three atoms selected from the group consisting of S, N, and O, c) an aryl having 6 to 10 carbon atoms, or d) a 5-6 membered aromatic heterocyclic moiety having a three atoms selected from the group consisting of S, N, and O, wherein the substituents (c) and (d) may be optionally substituted with carboxyl, halo, -CN, formyl, CF 3, -NO 2, -6-C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl; R92 and R93 at each occurrence are the same or different and represent a) H, b) phenyl, c) C1-6 alkyl, or d) benzyl; represents a) H-, b) ch3-, c) phenyl-CH2-, or d) CH3 C (O) 1 η -? R 2 represents a) (C 1 -C 3) alkyl-, or b) phenyl-; R104 represents a) H1478629 a) H-, or b) I or R106 represents a) CH3-C (O) -, b) HC (O) -, c) e) CH 3 SO 2 -, f) and (c)) g) F 2 CHC (O) -, h) C (O) -, k) D = C-CH 2 -CH 2 -C (O) m) phenyl-CH 2 -O-CH 2 -C (O) o C 1-4 alkyl-NH-C (S) - , or P) C 1-4 alkyl optionally substituted with one or more halo, CN, NO 2, OH, SH, or NH 2; R102-C (R101) (R111) -c (O) -, b) R103 O-C (O) -, c) R108 -C (O) -, 32 ΡΕ1478629

f) H 3 C-C (O) - (CH 2) 2 -C (O) -, g) R 109 -SO 2 -

i) HO-CH2-C (O) j) R116- (CH2) 2-, k) R113-C (O) -O-CH2-C (O) (C) aryl - (CH 2) n - (CH 2) n - (CH 2) n - (CH 2) n - , d) C H 2 C-, e) C 12 H 11 -, f) F H 2 C-, g) F 2 CH 3 - h) C 3-6 cycloalkyl, or CNCH 2 -. (i) R109 represents a) C1-C4 alkyl, b) -CH2 C1 -CH2 CH = CH2, d) aryl, or e-CH2 CN; R110 and R111 are independently a) H-, b) CH3-; or R 12 represents a) H-, b) CH 30 -CH 20 -CH 2 -, or c) HOCH 2 -; R113 represents a) ch3-, b) hoch2-, c) (CH3) 2 N -phenyl, or d) (CH3) 2 N-CH2-; R114 represents a) HO-, b) ch3-, c) h2n-, d) CH3 -C (O) -0, e) CH3 -C (O) -O-CH2 -C ) or -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -O- (CH 2) 2 -O-, CH2 -O-; ???????? R 1 is H), or b) C 1 -C? R116 represents a) H0- b) CH30-, or c) F; R150 and R151 are each independently a) H, b) C1 -C4 alkyl, or c) R150 and R151 taken together with the f atom to which R150 and R151 are attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms;

Each R300, R301, R302, R303, R304, R305, and R306 is independently selected from a) H, b) C3-6 cycloalkyl optionally substituted with = O, c) C1-6 alkoxy, d) optionally C1-10 alkyl substituted with one or more of R310, e) C2-10 alkenyl optionally substituted with one or more of R310, f) benzyloxycarbonyl, g) aryl, h) het, i) -C (O) -NR311R312, j) -S C (O) -R310, m) -C (S) -NR3nR3i2, n) -C (O) -H, or O) -C (O) ) -C 1-4 alkyl optionally substituted with one or more of R 31; R310 represents a) 10 > b) -n3, c) -cf3, d) pyridyl, e) halo, f) g) -O (O) C1-C6 alkyl, h) -C1-6 -alkyloxycarbonyl, i) -SH, j ) -nh2; Each R311 and R312 is independently selected from a) H, b) C1-4 alkyl, c) phenyl, or d) R3h and R312 together with the N atom to which they are attached form a saturated heterocyclic ring of 5 or 6 members optionally having one or more O, S, or N atoms in the ring, the heterocyclic ring being optionally substituted with C 1-3 alkyl; R315 represents a) H, b) C1-4 alkyl optionally substituted with halo, -OH, C1-8 alkoxy, amino, C1-8 alkylamino, or di-C1-8 alkylamino, c) aryl- S (O) 2 - (d) C (= O) -C1-4 alkyl, e) C (= O) O- C1-4 alkyl, f) C (= O) NHR32o, g) -OC (= O) -C1-4 alkyl, i) -S (O) -C1-4 alkyl, j) C1-4 alkyl-C1-4 alkyl, or k) C4-4 alkyl-S-C1-4 alkyl; R 32o is independently selected from a) H, or b) substituted alkyl;

Each R325, R326, R327, and R328 is independently selected from a) H, b) C1-C6 alkyl, c) substituted alkyl, d) halo, or e) R325 and R326 or R327 and R328 together represent = 0 or = S, or one of R325 or R326 and R3o3 when Z4 represents -N (R3o3> -f together with the carbon and nitrogen atoms to which they are attached form a 5-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S, or N; R330 represents a) H, or b) alkyl, or c) substituted alkyl; 37 ΡΕ1478629 R331 represents a) R332 r b) 1-1 c) nh2, d) OH, e) NHC1 -C4 alkyl, or f) R315; R332 represents a) H, b) C1-C4 alkyl, c) O-C1-C4 alkyl, d) S-C1-C4 alkyl, or e) NH-C1-4 alkyl R333 represents a) F, or b) R332 ; (B) halo, (c) C 1 -C 6 alkyl, (d) C 3 -C 6 cycloalkyl, (e) - (CH 2) l -OR 511, or (f ) -C (= O) -R 541; R5 and R5 represent each and independently (a) hydrogen atom, (b) C1 -C6 alkyl, (c) C1 -C6 alkoxy, (d) C1 -C6 alkylthio, (e) - (CH2) i-OR55i, 38 ΡΕ1478629 (f) -O- (CH2) l-OR551, (g) -NR542 R552, (h) -C (= O) -NR542 R552 (i) - (CH2) R541, or R501 and R502 taken together form (j) = 0, (k) = NR543 f (D = s, (m) = CR544 R554, or (n) a 5- or 6- membered saturated or unsaturated hetero ring having 1-3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom <1 and a sulfur atom; R 511 and R 512 each independently represent (a) hydrogen atom, (b) (B) - (CH 2) m -OH, (c) C 1 -C 8 alkyl, (d) C 1 -C 8 alkoxy, or (e) -O-CH 2 - R542 and R552 each represent, independently, (a) hydrogen atom, (b) - (CH2) t -OH, (c) C1 -C8 alkyl, (d) -C = O) -R5411 (e) -C (= O) -NR511R512, (f) - (C H2) q -phenyl, or 39 ΡΕ1478629 or R542 and R552 together form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, or a thiomorpholino group, each of which may be substituted by C1 -C6 alkyl or - (CH2) n -OH; R543 is (a) H, (b) -OR551, (c) C1 -C6 alkyl, (d) C1 -C6 alkoxy, (e) - (CH2) q -phenyl, (f) -NR542 R552 r (g) - NH-C (= NH) -NH 2, OR (h) [1,2,4] triazol-4-yl; R544 and R554 each represent, independently, a) H, (b) C1 -C6 alkyl, (c) -C (= O) -R541 r or (d) - (CH2) q -phenyl; R551 is (a) H, (b) C1 -C6 alkyl, (c) C1 -C6 alkyl substituted with 1-3 halo, (d) - (CH2) n -O R511, (e) - (CH2) 0) -R54I or (f) -C (= O) - (CH2) 1-OR544, R600 represents a) H, b) C1 -C4 alkyl c) het ΡΕ1478629 d) e) f) Reo and R602 (CH 2) b C (O) O-C 4 -C 4 alkyl, (CH 2) b C (O) C 4 -C 4 alkyl, or aryl; b) C 1 -C 4 alkyl, c) het, d) C 3 -C 6 cycloalkyl, e) aryl, f) O-C 1 -C 4 alkyl, g) C (O) O- C4-C4 alkyl or together together with each other form a cyclo- and R705 is independently h) R60i and R602 taken together with the carbon atom to which they are C3-C6 alkyl;

Each R700, R701, R702 and R703 is selected from a) H,

b) C4-4 alkyl optionally substituted with 1-3 halo, = O, = O, -OH H) C (O) NH2, d) -CN, e) aryl, f) substituted aryl, g) het, h) , or (i) R700 and R701 form = O or = S, or D R702 and R703 form = O or = S, or 41 ΡΕ1478629 m) R704 and R705 form = O or = S; a is 1 or 2; b represents 0 or 1; h represents 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; 1 is 1 or 3; m is 1, 3, 4 or 5; n is 0, 1, 2, 3, 4, or 5; P represents 0, 1, 2, 3, 4, or 5; with the proviso p together are 1, 2, 3,4, or 5; q is 1, 2, 3, or 4; t is 0, 1, 2, 3, 4, 5, or 6; and w represents 0, 1, 2, or 3.

Embodiments of this aspect of the invention may include one or more of the following embodiments. 21. R2 is independently selected from H, F, Cl, Br, CN, NH2, NO2, CF3, and CH3. The structure of A is

O \

D

N 0 * -A or

\ N &quot; ' &quot; oI- *. The structure of A is H, -NH2, -OH, C1-4 alkyl, C3-5 cycloalkyl, C1-4 alkoxy, or C2-4 alkenyl, the alkyl and substituted alkoxy being each substituted with one or more halo , -OH, -CN. R 1 represents H -OH, -CH 2 -CH = CH 2, methyl, ethyl, propyl, -CH 2 -CH 2 F, -CH 2 -CH 2 OH, represents methoxy.

Ri

B ΡΕ1478629 - 42 - ^ <0ΗΛ Jl / R "

% SQ

Β is selected from

ΡΕ1478629 43

B and an R2 form 44 ΡΕ1478629

B and R2 form -C (O) -N (R300) -OC (O) -N (R3oo) -f -N (R106) -HCR30-CH2-, -NR300 -C (O) -C (R327R328) (O) -C (O) -C (O) -C (R 327 R 328) -S-, -NR 300 -C (S) -C (R 327 R 328) -S-, -NR 3 O-C (O) -CH 2 -CH 2 -NR 10 7 -CH 2 -CH 2 -, or -CH 2 -NR 10 7 -CH 2 -CH 2 -CH 2 -. Dl represents S. Di is O. R 300 represents C 1-4 alkyl such as methyl, ethyl, or isopropyl. One R2 represents hydrogen and the other R2 represents F. Both R2 substituents represent F.

Other aspects of the invention include pharmaceutical compositions comprising a compound of formulas I, II or III and a pharmaceutically acceptable carrier and methods for the treatment of bacterial infections in mammals by administering an effective amount of a compound of formulas I, II, or III. The compound may be administered to a mammal orally, parenterally, transdermally, or topically in a pharmaceutical composition. The compound may be administered in an amount of 45 Å AND 147 7 299 of from about 0.1 to about 100 mg / kg body weight / day, such as in an amount of from about 1 to about 50 mg / kg body weight / day .

Specific compounds of the invention include but are not limited to the following. (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-methyl-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-allyl-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-propyl-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-methoxy-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-hydroxy-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3,5-Difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [4- (3-Pyridyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [4- (4-Pyridyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [4- (3,6-Dihydro-2 H -pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 46 ΔΕ1478629 (5R) - (-) - 3- [4- (Tetrahydro-2 H -pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (3,6-Dihydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide; 5.5 (5R) - (-) - 3- [4- (3,6-Dihydro-2 H -3-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) - (-) - 3- [4- (tetrahydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (eis-tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5 (5R) - (-) - 3- [4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (cis -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (trans-tetrazol-2-yl) -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) - (-) - N-methyl-3- [4- (tetrahydro-2H-thio-pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) -3- [3,5-Difluoro-4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide dioxide; (5R) - (-) - 3- [3,5-Difluoro-4- (cis -tetrahydro-1-oxido-2-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide ; (5R) - (-) - 3- [3,5-Difluoro-4- (trans -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3,5-difluoro-4- (trans -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (cis-1- (methylimino) -1-oxido-1,3,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3-fluorophenyl] ] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (cis-1-imino-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3 -fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (Cyclohexyl-1-oxido-1,1,3,4,5,6-hexahydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2 oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (cis-1- (methylimino) -1-oxido-1,3,3,4,5,6-hexahydro-2 H -pyranan-4-yl ) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (trans-1- (imino) -1-oxido-1,3,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3-fluorophenyl] ] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (trans-1- (imino) -1-oxido-1,3,3,4,5,6-hexahydro-2 H -pyranan-4-yl ) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (trans-1- (methylimino) -1-oxido-1,3,3,4,5,6-hexahydro-2 H -pyrazan-4-yl) -3- fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (trans-1- (methylimino) -1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) -3- [4- (3,6-Dihydro-2 H -thiopyran-4-yl) -3,5-difluorophenyl] -N-methyl-2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) -3- [4- (3,6-Dihydro-2 H -thiopyran-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Metyl-3- [3-fluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [4- (thiomorpholin-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) - (-) - 3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide dioxide; 5.5 (5R) - (-) - 3- [3-Fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide; (5R) -3- [3-Fluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3-Fluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3-Fluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3,5-Difluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3,5-Difluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3,5-Difluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3,5-Difluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5 R) - (-) - 3- [3,5-Difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide; (5 R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide; 5.5- (5R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; 49 ΡΕ1478629 (5R) - (-) - 3- (2,3-Dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- (2,3-Dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- (2,3-Dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-methyl-2-pyrrole-3-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Ethyl-3- (2,3-dihydro-3-methyl-2-pyridin-2-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N- (2-Hydroxyethyl) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N- (2-Fluoroethyl) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; 50 ΔΕ1478629 (5R) - (-) - 3- (2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- (2,3-Dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- (2,3-Dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-methyl-2-pyridin-2-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3 - [(2R) -2,3-Dihydro-1-formyl-2-methyl-1H-indol-5-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3 - [(2R) -2,3-Dihydro-1- (hydroxyacetyl) -2-methyl-1H-indol-5-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (5,7-Dihydro-6 H -pyrrolo [3,4-b] pyridin-6-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (5,7-dihydro-6-pyrrolo [3,4-b] pyridin-6-yl) -3-fluorophenyl] -2-oxo-5- oxazolidinecarboxamide; (5R) - (-) - 3- [3,5-Difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3,5-Difluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3,5-difluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3-fluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- [3,5-difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (3,4-Dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N- (2-Fluoroethyl) -3- (3,4-dihydro-4-methyl-3-oxo-2,1-benzoxazin-7-yl) -2-oxo-5- oxazolidinecarboxamide; (5R) -3- (3,4-Dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,2-Difluoro-4-methyl-3,4-dihydro-3-oxo-2-1,7-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide ; (5R) -N-Methyl-3- (2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2,11-benzoxazin-7-yl) -2-oxo-5- oxazolidinecarboxamide; 52 ΡΕ1478629 (5R) -3- (8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (4-Methoxy-3-thioxo-3,4-dihydro-2,7-1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3,4-dihydro-4-methyl-3-oxo-2-yl) -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2-yl-1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3,4-dihydro-5-fluoro-4-methyl-3-oxo-2,1-benzothiazin-7-yl) -2-oxo-5- oxazolidinecarboxamide; (5R) -3- (3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2,1-l4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3,4-dihydro-5-fluoro-4-methyl-3-oxo-2,1-benzoxazin-7-yl) -2-oxo-5- oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (5-oxo-5,6-dihydro-4H- [1,3,4] thiadiazin-2-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide ; (5R) -3- [4- (1,1-Dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl) -3,5-difluorophenyl] -2-oxo-5- oxazolidinecarboxamide; (5R) -3- [4- (2,5-Dihydro-1H-pyrrol-1-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; 53 ΡΕ1478629 (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N- (2-Fluoroethyl) -3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- [3,4-Dihydro-4- (hydroxyimino) -1 (2H) -pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2-Formyl-2,3,4,5-tetrahydro-1-2-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2-formyl-2,3,4,5-tetrahydro-1-2-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [2- (Hydroxyacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [2- (hydroxyacetyl) -2,3,4,5-tetrahydro-1-2-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (3-Formyl-2,3,4,5-tetrahydro-3-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3-formyl-2,3,4,5-tetrahydro-3-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3- (Hydroxyacetyl) -2,3,4,5-tetrahydro-3-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3- (hydroxyacetyl) -2,3,4,5-tetrahydro-1-benzyl-3-oxazolidinecarboxamide; (5R) -3- [4- (1- (2 (S) -Hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl] -2 oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (1- (2 (S) -hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl] -2 oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (1- (2 (S), 3-Dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl] -2- oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5- difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (1- (2 (S) -Hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] -2-oxo -5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (1- (2 (S) -hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] -2-oxo -5-oxazolidinecarboxamide; (5R) -3- [4- (1- (2 (S), 3-Dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] -2-oxo -5-oxazolidinecarboxamide; and (5R) -N-Methyl-3- [4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl ] -2-oxo-5-oxazolidinecarboxamide.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions have been used, less 55 ΡΕ1478629 than otherwise described.

Variables including a letter followed by a higher numeric index are equivalent to the same letter followed by the same number as a lower numeric index. For example, Ri and Ri are equivalent and refer to the same variable. The carbon atom content of various hydrocarbon containing moieties may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, ie, the prefix C 1 2 denotes a portion of carbon atoms of the integer &quot; i &quot;; to the integer &quot; j &quot; inclusive. Thus, for example, C 1-7 -alkyl refers to alkyl of from one to seven carbon atoms, inclusive. The term &quot; halo &quot; refers to a halogen atom selected from Cl, Br, I, and F. The term &quot; alkyl &quot; refers to either straight or branched chain moieties. Unless otherwise stated, such as by a prefix C1-3, alkyl portions include from 1 to 6 carbon atoms. The term &quot; alkenyl &quot; refers to both straight and branched chain moieties containing at least one -C = C-. Unless otherwise stated, such as by means of a C1-3 prefix, alkenyl moieties include between 2 and 566 ΡΕ1478629 carbon atoms. The term &quot; alkynyl &quot; refers to both straight and branched chain moieties containing at least one -C = C-. Unless otherwise stated, such as by means of a C1-3 prefix, alkynyl moieties include from 2 to 6 carbon atoms. The term &quot; alkoxy &quot; refers to -O-alkyl groups. Unless otherwise stated, such as by a prefix C-1, the alkyl portion of the -O-alkyl group includes from 1 to 6 carbon atoms. The term &quot; amino &quot; refers to NH2. The term &quot; cycloalkyl &quot; refers to a cyclic alkyl moiety. Unless otherwise stated, such as by a prefix C12, cycloalkyl moieties will include from 3 to 7 carbon atoms. The term &quot; cycloalkenyl &quot; refers to a cyclic alkenyl moiety. Unless otherwise stated, such as by means of a C1-3 prefix, cycloalkenyl moieties will include between 3 and 7 carbon atoms and at least one -C = C- group within the cyclic ring. The term &quot; aryl &quot; refers to phenyl and naphthyl. The term &quot; het &quot; refers to monocyclic or bicyclic ring systems containing at least one heteroatom selected from O, S, and N. Each monocyclic ring may be aromatic, saturated, or partially unsaturated. A bicyclic ring system may include the monocyclic ring containing at least one heteroatom which is fused to a cycloalkyl or aryl group. A bicyclic ring system may also include the monocyclic ring containing at least one heteroatom fused to another het monocyclic ring system.

Examples of &quot; het &quot; include but are not limited to pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4- pyridazinyl, 3-pyrazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxazolyl, 2-oxazolyl, 1,2-oxazolyl, 1,2,3-oxathiozole, 1,2,3- 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl, 3-furanyl, 2-thienyl, 3- thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrroloyl, 1,2,3-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2 Oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3- oxo-1,2,4-thiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2 , 4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4- tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-iso-4-thiazolyl, 5-isothiazolyl, 1,3,4-oxadiazole, 4-oxo-2-thiazolinyl, 5-methyl- 2-yl, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone, phthalimide, quinolinyl, morpholinyl, benzoxazoyl, diazinyl, triazinyl, quinolinyl, quinoxalinyl, naphthyridinyl, azetidinyl, pyrrolidinyl , hydantoinyl, oxathiolanyl, dioxolanyl, imidazolidinyl, and azabicyclo [2.2.1] heptyl. The term &quot; heteroaryl &quot; refers to an aromatic het, examples of which include, but are not limited to, pyridine and thiophene. The term &quot; substituted alkyl &quot; refers to an alkyl moiety including 1-4 substituents selected from halo, het, cycloalkyl, cycloalkenyl, aryl, -OCO, -SO, -S (O) 2 O, -S (O) ) O, -C (= N O) O, -C (= NOH) Q 10, -C (O) Q 10, -NO 10 O, -C (O) Q 10, -CN, = O, = S, -NQ 1 C (O) Q 1, -NO 2 C (O) N O] O] -S (O) 2 NQ10Q101 -NQ10S (O) 2Qicu -NQ10S (O) Q10, -NQ10SQ10, -NO2, -0P0 (OH) 2, and -SNQ10Q10. Each of het, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-4 substituents independently selected from halo and Q15. The term &quot; substituted aryl &quot; refers to an aryl moiety having 1-3 substituents selected from -OQ10, -SQ10, -S (O) 2 O, -S (O) Q10, -OS (O) C (= NH) Q10, -SC (O) Q10, -NQ10Q10, -C (O) QiO, -C (S) Q10.59 ΡΕ1478629 -C (Ο) O8io, -OC (O) Q10, -C (O) C (O) C (Qi) 2 OC (O) Q 10, -CN, -NO 10 C (O) Q 10 R NQ 10 C (O) NQ 10 Q 10, -S (O) 2 NQ 10 Q 10, NQ10 S (O) Q10, -NQ10SQ10, -NO2, -SNQio, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3 substituents selected from halo and Q15. The term &quot; het substituted &quot; refers to a het moiety including 1-4 substituents selected from -OQ10, -SQ1 O, -S (O) 2 O, -S (O) Q10, -OS (O) 2 O, -C (= (= NOH) Q 10, -C (O) Q 10, -NO 10 Q 10, -C (O) Q 10, -C (O) Q 10, -C (O) O Q 10, -OC (O) Q 10, -C (O) NQ 10 Q 10 , -C (O) C (Qi) 20C (O) Q 10, -CN, -NO 10 C (O) Q 10, -NO 10 C (O) N 8 io, -S (O) 2 NQ 10 Q 10, -NQ 10 S (O) O) Q 10, -NO 10 SQ 10, -NO 2, -SNQ 10 Q 10, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyl, and aryl. Substituted het may also be substituted by one or more substituents = O or = S provided the 0 or S are attached to ring atoms capable of carrying a double bond between the ring atom and 0 or S. Hets, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3 substituents selected from halo and Q15. The term &quot; substituted alkenyl &quot; refers to an alkenyl moiety including 1-3 substituents -OQ10, -SQ10 # · -S (O) 2Q10, -S (O) Q10, -OS (O) 2 O, -C (= NQ 10) Q 10, -SC (O) Q10, -C (O) Q10, -C (O) Q10, -C (O) O Q10, -OC (O) ) 20C (O) Q 10, -CN, = O, = S, -NQ 1 C (O) Q 10, 60 ΡΕ1478629 -NQ10C (Ο) NQ10Q101 -S (O) 2NQ10Q10A -NQ10S (O) NQ10SQ10, -NO2, -SNQioC10 alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3 substituents selected from halo and Q15. The term &quot; substituted alkoxy &quot; refers to an alkoxy moiety including 1-3 substituents -OQ10, -SQ10, -S (O) 2 O, -S (O) Q10, -OS (O) 2 O, -C (= NQ 10) Q 10, -SC 0) Q10, -C (O) Q10, -C (O) Q10, -C (O) Q10, -C (O) OQ10, -OC (O) Q10, 2 O (O) Q 10, -CN, = O, = S, -NO 10 C (O) Q 10, -NO 10 C (O) N 10 10, -NQ10SQ10, -NO2, -SNQ10Q10, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3 substituents selected from halo and Q15. The term &quot; substituted cycloalkenyl &quot; refers to a cycloalkenyl moiety including 1-3 substituents -OQ10, -SQ10, -S (O) 2 O, -S (O) Q10, -OS (O) 2 O, -C (= N OX) ) Q10, -C (O) Q10, -C (O) Q10, -C (O) QiO, -C (O) O QiO, -OC (O) QiO, -C (O) (O) Q 10, -CN, = O, = O, -NO 10 C (O) Q 10, -NO 10 C 10, -NO 10 C (O) -NQ10SQ10, -NO2, -SNQ10Q10, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3 substituents selected from halo and Q15. The term &quot; substituted amino &quot; refers to an amino moiety in which one or both of the amino hydrogens are substituted with a group selected from -O-O-R 10, -S (O) 2 O, -S (O) Q 10, -OS (O) (O) O-C (O) Q 10, -C (O) Q 10, -C (O) C 10 O-C (O) O) Q 1, -CN, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3 substituents selected from halo and Q15.

Each Q10 is independently selected from -H, alkyl, cycloalkyl, het, cycloalkenyl, and aryl. The het, cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3 substituents selected from halo and Q13.

Each Q n is independently selected from -H, halo, alkyl, aryl, cycloalkyl, and het. The alkyl, cycloalkyl, and het may be optionally substituted with 1-3 substituents independently selected from halo, -NO2, -CN, = S, = O, and Q14. The aryl may be optionally substituted with 1-3 substituents independently selected from halo, -NO 2, -CN, and Q 1 4

Each Q13 is independently selected from Qn, -OQ, -SQ, -S (O) 2Qn, -S (O) Qh, -OS (O) 2Qn, -C (= NQn) Qn, -SC (O) Qn, -OC (O) Qn, -C (O) NQnQn, -C (O) C (O) ) 0OC (O) Q1, -CN, = O, = S, -NQnC (O) Qn, -NQnC (O) NQnQn, -S (O) 2NQnQn, -NQnS (O) 2Qn, -NQH S (O) Qn , -NQnSQn, -NO2, and -SNQQn, provided that Q13 does not represent = O or = S when Q10 represents aryl or a het which lacks any atom capable of forming a double bond with 0 or S.

Each Q14 is -H or a substituent selected from alkyl, cycloalkyl, cycloalkenyl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -Cl, -Br, -I (O) 2 Q 6, -C (O) Q 1 6, -C (O) Q 1 6, -C (O) (O) NQ 16 Q 16, -S (O) 2 NQ 16 Q 16, and -NQ 16 S (O) 2 Q 16 • Alkyl, cycloalkyl, and cycloalkenyl may be further substituted with = O or = S.

Each Q15 represents alkyl, cycloalkyl, cycloalkenyl, het, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -Cl, -Br, -I, -O-Q6, -SQ16, -S (O) Q 16, -OS (O) Q 16, -O S (O) 2 Q 16, -C (= NQ 16) Q 16, -SC (O) Q 16, , -C (O) O Q 16, -O C (O) Q 16, -C (O) -NQieQie, -C (O) C (Q 1) 20 C (O) Q 1, -CN, -NQ 16 C (O) Q 16, -NQ 16 C (O) Q 16, -NQ 16 Q 16, -NO 2, and -SNQ 16 Q 16. The alkyl, cycloalkyl, and cycloalkenyl groups may be further substituted with = 0 or = S. 63 ΡΕ1478629

Each Q16 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl may additionally include 1-3 halos.

Specific R2 substituents include H, F, Cl, Br, -CN, -NH2, -NO2, -CH3.

Specific structures of A include

Mammal refers to humans or animals.

The compounds of the present invention are generally referred to according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art (eg &quot; Ph &quot; for phenyl, &quot; Me &quot; for methyl, &quot; Et &quot; for ethyl, &quot; for &quot; oxygen atom, &quot; for nitrogen atom, &quot; h &quot; for hour or hours and &quot; ta &quot; for room temperature). It is to be understood that the present invention encompasses any racemic, optically active, poly-morphic, tautomeric, or stereoisomeric form, or a mixture thereof, of a compound of the invention having the properties described herein.

The compounds of the present invention may be converted into their salts, where appropriate, according to conventional methods.

In cases where the compounds are sufficiently basic or acidic to form stable, non-toxic salts with acids or bases, the use of the compounds in the form of pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts which are within the scope of the present invention include addition salts with organic acids formed with acids which form a physiologically acceptable anion and inorganic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, the following acids: acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bis-sulfuric, bitartaric, butyric, calcium, camthalic, carbonic, chlorobenzoic, citric, edético esters, esyl, esyl, esyl, formic, fumaric, gluconic, gluconic, glutamic, glycolylarsanilic, hexamic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactobionic, maleic, malic, malonic , methylene sulfonic, methylnitrile, methylsulfuric, mucic, muconic, napsic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, phthalic, polygalactyronic, propyl, salicylic, stearic, succinic, sulfamic, sulphanilic, sulfonic, sulfuric, tannic, tartaric, theoolic and toluene . Examples of pharmaceutically acceptable salts include, but are not limited to, the following bases: primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine , diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucine, morpholine, piperazine, piperidine, polyamine resins , procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like. The pharmaceutically acceptable salts may be in hydrated form.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reaction with a sufficiently basic compound such as an amine with an acid suitable to provide a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g. calcium) salts of carboxylic acids may also be made.

The compounds of formula I of this invention contain a guiral center, such as at the C-5 of the oxazolidinone ring, and as such there are two enantiomers or a racemic mixture thereof. This invention also relates to the enantiomer having the useful properties described herein, as well as to mixtures containing both isomers. In addition, depending on the substituents, additional chiral centers and other isomeric forms may be present in any of the groups A, B, or R1, and this invention encompasses all possible stereoisomers and geometric forms in these groups.

The compounds of this invention are useful for the treatment of bacterial infections in humans and other warm-blooded animals.

Dosages and Pharmaceutical Compositions

By the phrase &quot; effective amount &quot; of a compound as provided herein is meant a non-toxic but sufficient amount of one or more compounds of this invention to provide the desired effect. The desired effect may be to prevent, give relief from, or ameliorate bacterial infections.

As indicated below, the exact amount of the compound of this invention required to treat a bacterial infection will vary from individual to individual, depending on the species, age, and general condition of the subject, the severity of the disease being treated, the particular compound (s) used, and the mode of administration, such as the route and frequency of administration, and the like. In this way, it is not possible to specify an exact effective amount. However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.

The pharmaceutical compositions of this invention may be prepared by combining the compounds of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid support may be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Solid inert carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, solutions of the compounds of this invention dissolved in water and water-propylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents may be provided.

Preferably, the pharmaceutical composition is provided by conventional techniques in dosage unit form containing effective or appropriate amounts of the active component, i.e., the compound according to this invention. The amount of the active component, i.e. the compound according to this invention, in the pharmaceutical composition and its dosage unit form may be varied widely or adjusted depending on the particular application, potency of the particular compound and the desired concentration. Generally, the amount of the active component will range from 0.5% to 90% by weight of the composition.

In therapeutic use to treat, or combat, bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and / or topically in a dosage to obtain and maintain a concentration, i.e., a quantity, or level in the blood of the active component in the animal to be subjected to treatment which is antibacterially effective. Generally, such an antibacterially effective dosage amount of active ingredient will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg / kg body weight / day. It is to be understood that the dosages may vary depending on the needs of the patient, the severity of the bacterial infection to be treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper limit in order to rapidly reach the desired level in the blood or the initial dosage may be less than optimal and the daily dosage can be progressively increased during the course of the treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 times per day.

A specific active agent may have more than a recommended dosage range, particularly for different routes of administration. Generally, an effective dosage amount of compounds of this invention, whether administered individually or in combination with other inhibitor compound (s), will be in the range of about 5 to about 2500 mg / day, more specifically about from 10 to about 750 mg / day, and most conveniently from 50 to 500 mg per unit dosage form. It is to be understood that the dosages of the active component (s) may vary depending on the needs of each individual to be treated and the severity of the microbial infection. Initial treatment of a patient suffering from microbial infection may begin with a dosing regimen as indicated above. Treatment is generally continued as needed over a period of several days to several months until the condition or disorder has been controlled or eliminated. Patients to be treated with the composition of the invention may be routinely monitored by any of the methods known in the art to determine the efficacy of the therapy. Continued analysis of data from such monitoring allows the modification of the treatment regimen during therapy so that optimally effective amount of drug is administered at any point in time, and so that the duration of treatment can be determined. Accordingly, the treatment regimen and the dosing schedule may be rationally modified throughout the course of the therapy so that the lowest amount of the compounds of this invention which is respiratory efficacious is administered, and so that administration is continued only in the to the extent that it is necessary to successfully treat the condition or disorder.

In a combination therapy, the compound (s) of this invention and other inhibitor compound (s) may be administered simultaneously or at separate intervals. When simultaneously administering the compound (s) of this invention and the other inhibitor compound (s) may be incorporated into a single pharmaceutical composition or into separate compositions, eg, compound (s) of this invention in one composition and the other inhibitory compound (s) in another composition. For example, the compound (s) of this invention may be administered concurrently or concomitantly with the other inhibitor compound (s). The term &quot; concurrently &quot; means that the subject being treated takes a drug within about 5 minutes of taking the other drug. The term &quot; concomitantly &quot; means that the subject being treated takes one drug within the same treatment period of taking the other drug. The same treatment period is preferably within twelve hours and up to forty-eight hours.

When administered separately, therapeutically effective amounts of the compound (s) of this invention and the other inhibitor compound (s) are administered at a different time. One may be administered before the other such that the time between the two administrations falls within a therapeutically effective range. A therapeutically effective range is a period of time that begins when one of (a) the compound (s) of this invention, or (b) the other inhibitory compound (s) is administered to a mammal and ends at the limit of the beneficial effect in the treatment of bacterial infections of the combination of (a) and (b). The methods of administering the compound (s) of this invention and the other inhibitor compound (s) may be varied. Thus, one agent can be administered orally, while the other is administered by injection.

In addition to the compounds of this invention and other antimicrobial agents, the pharmaceutical composition for therapeutic use may also comprise one or more pharmaceutically acceptable non-toxic carrier materials or excipients. The term material &quot; support &quot; or &quot; excipient &quot; means either any substance which is not in itself a therapeutic agent used as a carrier and / or diluent and / or adjuvant, or vehicle for administration of a therapeutic agent to an individual or added to a pharmaceutical composition for improving its handling or storage properties or to enable or facilitate the formation of a dosage unit of the composition in a discrete article such as a capsule or tablet suitable for oral administration. Excipients may include, by way of illustration and not limitation, diluents, disintegrators, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or neutralize an unpleasant taste or odor, flavors, colorants, fragrances , and added substances to enhance the appearance of the composition. Suitable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl esters of cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts, phosphoric and sulfuric acids, gelatin, gum acacia, sodium alginate, polyvinyl pyrrolidone, and / or polyvinyl alcohol, and then compressed or encapsulated for convenient administration. The capsules or tablets may contain a sustained release formulation which may be provided in a dispersion of active compound in hydroxypropylmethylcellulose, or other methods known to those skilled in the art. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. If desired, other active ingredients may be included in the composition. 73 ΡΕ1478629

ROUTES OF ADMINISTRATION

In therapeutic use to treat, or combat, infections in a mammal (i.e., humans and animals) the pharmaceutical composition may be administered orally, parenterally, topically, rectally, or intranasally.

In addition to the oral dosage mentioned above, the compositions of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and at a dose effective for the intended treatment. The compositions may, for example, be administered parenterally, e.g. intravascularly, intraperitoneally, subcutaneously, or intramuscularly. For parenteral administration, saline, dextrose solution, or water may be used as a suitable carrier. Formulations for parenteral administration may be in the form of sterile, aqueous or non-aqueous isotonic solutions or suspensions for injection. These solutions and suspensions may be prepared from stable powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. 74 ΡΕ1478629

Generally, the concentration of each of the compounds of this invention in a liquid composition, such as a lotion, will be from about 0.1% by weight to about 20% by weight, preferably from about 0.5%, by weight, to about 10% by weight. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers. The concentration in a semi-solid or solid composition, such as a gel or a powder, will be about 0.1% by weight to about 5% by weight, preferably about 0.5% by weight, to about 2.5% by weight. When topically administered, the pharmaceutical composition of the present invention to be used to effect targeted treatment of a specific internal site, each of the compounds of this invention is preferably contained in the composition in an amount of from 0.05-10% by weight, more preferably 0 , 5-5% by weight.

Parenteral administrations include injections to generate a systemic effect or injections directly into the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intravetricular, and general infusion techniques.

Topical administrations include treatment of infectious areas or organs easily accessible by local application, such as, for example, in the eyes, ears including external and middle ear infections, vaginal, open and sutured or closed wounds, and skin. Transdermal administration is also included to generate a systemic effect. Rectal administration includes the form of suppositories. Intranasal administration includes nasal aerosol or inhalation applications.

Pharmaceutical compositions including the compounds of this invention may be prepared by methods well known in the art, e.g., by means of conventional blending, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, sequestration, lyophilizing or spray drying processes.

The pharmaceutical compositions for use according to the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of the active compounds into preparations which may be used pharmaceutically. The appropriate formulation is dependent on the chosen route of administration.

For oral administration, the compounds of this invention may be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, lozenges, capsules, liquids, solutions, emulsions, gels, syrups, slurries, slurries, and the like, for oral ingestion by a patient. A carrier may be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Examples of such carriers or excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatine, cellulosic materials, low wax melting point, cocoa butter or powder, polymers such as polyethylene glycols and other acceptable pharmaceutical materials.

Dragee cores are provided with suitable coatings. To this end, concentrated sugar solutions may optionally be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or mixtures of solvents.

Coloring matter or pigments may be added to the tablet or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and the plasticizer, such as glycerol or sorbitol. The &quot; push-fit &quot; may contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides. Stabilizers may also be added in these formulations.

Liquid form compositions include solutions, suspensions and emulsions. For example, solutions of pharmaceutical compositions may be provided with the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.

The compounds of this invention may also be formulated for parenteral administration, e.g., by injections, bolus injection or continuous infusion. Formulations for parenteral administration may be presented in dosage unit form, e.g., in ampoules or in multi-dose packages, with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation materials such as suspending, stabilizing and / or dispersing agents.

For injection, the compounds of this invention may be formulated in aqueous solution, preferably in physiologically compatible buffers or in physiological saline buffer. Suitable buffers include tri-sodium orthophosphate, sodium bicarbonate, sodium citrate, N-methyl glucamine, L (+) - lysine and L (+) - arginine.

The compositions may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or salts thereof can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions may also be made into glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and oils. Under usual conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Suitable pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. At all, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The carrier or liquid carrier may be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glyceryl esters , and mixtures thereof. Adequate fluidity may be maintained, for example, through the formation of liposomes, by maintaining the required particle size in the case of dispersions or by the use of surfactants. Prevention of the action of microorganisms can be effected by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions may be effected by use in the compositions of agents which retard absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization by filtration. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredient present in the previously sterilized solutions by filtration.

Other parenteral administrations also include 80 ΡΕ1478629 aqueous solutions in a water soluble form, such as, without limitation, a salt, of the compounds of this invention. In addition, suspensions of the active compounds can be prepared in a lipophilic carrier. Suitable lipophilic vehicles include fatty oils such as sesame oil, esters of synthetic fatty acids such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous suspensions for injection may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and / or agents which increase the solubility of the compounds to enable the preparation of highly concentrated solutions.

Alternatively, the compounds of this invention may be in powder form for constitution with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

For administration of suppositories, the pharmaceutical compositions may also be formulated by mixing the compounds of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum in order to release the drug. Such materials include cocoa butter, beeswax and other glycerides.

For administration by inhalation, the compounds of this invention may conveniently be administered by an aerosol spray in the form of a solution, dry powder, or cream. The aerosol may use a pressurized pack or a nebulizer and a suitable propellant. In the case of a pressurized aerosol, the dosage unit can be controlled by the provision of a valve in order to administer a measured amount. Capsules and cartridges, for example, gelatin for use in an inhaler may be formulated containing a powder base such as lactose or starch.

For ophthalmic and otitis use, the pharmaceutical compositions may be formulated as micronized suspensions in sterile, isotonic, pH adjusted saline, or preferably as solutions in sterile, isotonic, pH adjusted saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated into an ointment, such as petrolatum.

In addition to the formulations described above, the compounds of this invention may also be formulated as depot preparations. Such long acting formulations may be in the form of implants. The compounds of this invention may be formulated for this route of administration with suitable polymers, hydrophobic materials, or as a sparingly soluble derivative such as, without limitation, a poorly soluble salt.

In addition, the compounds of this invention may be administered using a sustained release system. Various materials for sustained release have been established and are well known to those skilled in the art. Prolonged release capsules may, depending on their chemical nature, release the compounds for 24 hours to several days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for stabilizing proteins may be employed. In certain embodiments, the compounds of this invention are applied topically. For topical applications, the pharmaceutical composition may be formulated into a suitable ointment containing the compounds of this invention suspended or dissolved in one or more carriers. Supporters for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated into a suitable lotion such as suspensions, emulsion, or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The antibacterial agents of this invention possess useful activity against a number of organisms. The in vitro activity of compounds of this invention can be evaluated by standard assay procedures such as 83 ΡΕ1478629 determination of the minimal inhibitory concentration (MIC) by dilution of agar as described in &quot; Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically &quot;, 3a. ed., published in 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania, USA.

The following Diagrams describe the preparation of compounds of the present invention. The starting materials are prepared by the procedures described in these diagrams or by procedures known to one of ordinary skill in the art.

DIAGRAM I 84 ΡΕ1478629

DIAGRAM I illustrates methods for the preparation of aryloxazolidinone-5-carboxamides 5 and their N-substituted derivatives. In METHOD A, aryl-carbamate derivatives 1 (B4 = C1-6 alkyl or benzyl) (known in the literature, prepared by known methods such as by derivatization of aniline 6, or described in the following diagrams) may be deprotonated with a lithium base such as n-butyl lithium in a suitable solvent such as THF at a suitable temperature, typically in the range of -78 ° C to -40 ° C, to give a lithiated species which is 85 ΡΕ1478629 directly treated with potassium (2R) -glycidate (<J. Org. Chem. 1992, 57 (12), 3380-3387). Heating to room temperature and stirring for a suitable period of time affords the aryl oxazolidinone-5 (R) -carboxylic acids. The acids 3 can then be converted into the desired structures 5 using methods known to those skilled in the art. For example, treatment of the acids 3 with oxalyl chloride under an inert atmosphere provides the acid chloride intermediates which may be converted to the amides 5 (R 1 = H or optionally substituted alkyl) following treatment with optionally substituted ammonia or alkyl amines (R 1 NH 2) or hydroxamates 5 (R1 = Oalkyl) following treatment with O-alkylhydroxylamines. The hydroxamate derivatives can also be prepared directly from the acids 3 after treatment with an O-alkylhydroxylamine (or its hydrochloride salt) in the presence of a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride . When R 1 represents O-benzyl, hydrogenolysis of 5 then affords the hydroxamic acid derivatives (R 1 = OH). Alternatively, the 3-acids can be converted into the desired structures 5 through the ester intermediates 4 (B5 = methyl, ethyl, propyl, butyl, for example) using methods known to those skilled in the art. For example, the methyl esters 4 (B5 = Me) can be prepared by treating methanolic solutions of the acids 3 with an acid catalyst such as sulfuric acid at room temperature. Subsequent treatment 86 ΡΕ1478629

with amines R1NH2 in a suitable solvent such as methanol or acetonitrile then affords the amides 5 (R1 = H or optionally substituted alkyl). Similarly, treatment with hydrazine gives the hydrazides 5 (R 1 = NH 2).

In METHOD B, (5R) -hydroxymethyl-aryl-oxazolidinones 2 may be oxidized using, for example, chromium (VI) / sulfuric acid in a solvent system such as acetone / water (EP 0 437 410 A; 417 044 A) or ruthenium (III) chloride (cat.) / Sodium periodate in the presence of sodium dihydrogenphosphate in a solvent system such as acetonitrile / methylene chloride / water (See U.S. Patent No. 5,614,535) to afford the aryl-oxazolidinone-5 (R) -carboxylic acids 3 which can then be converted into the desired structures 5, as previously described. The (5R) -hydroxymethyl-aryl-oxazolidinone 2 starting materials can be obtained by treating the aryl carbamates 1 with a lithium base such as n-butyllithium or lithium hexamethyldisilazide in a solvent such as THF at a temperature , typically in the range of from -78 ° C to -40 ° C, to give a lithiated species which is directly treated with (R) -glycyl butyrate. Heating up to room temperature, then provides the structures 2.

In METHOD C, anilines 6, which are known in the literature or produced by known methods (see also the following diagrams), may be converted to 87 ΡΕ1478629 structures 7 following treatment with an alkyl (2R) -epoxypropanoate and lithium triflate in a suitable solvent such as acetonitrile at a suitable temperature, typically in the range of from 20øC to 110øC depending on the solvents. Amino alcohols 7 may then be subjected to ring closure to give the aryl oxazolidinones 4 using methods known to a person skilled in the art. For example, treatment of structures with 1,1'-carbonyldiimidazole in a solvent such as acetonitrile or THF at a suitable temperature, typically in the range of 20Â ° C to 60Â ° C, or with phosgene in a solvent such as toluene or chloride of methylene, or mixtures thereof, in the presence of a base such as triethylamine at a suitable temperature, typically in the range of from -10øC to 25øC, affords the oxazolidinones 4. The structures 4 may then be converted into the compounds by using the previously described methods.

DIAGRAM II

EXAMPLE II illustrates the preparation of thiopyran-4-yl-phenyl-oxazolidinone-5-carboxamides 10 and 11. (3,6-Dihydro-2 H -thiopyran-4-yl) phenylcarbamates EXAMPLE VII and IX) can be converted to the oxazolidinone-5-carboxamide 9 using steps similar to those described in DIAGRAM I for the conversion of 1 in 5 using METHOD A. The sulfur group in the structures 9 can then be oxidized with a suitable oxidizing agent such as sodium periodate in an appropriate solvent such as mixtures of methanol and water or osmium tetroxide (cat.) and N-methylmorpholine N-oxide in an appropriate solvent such as as mixtures of acetone and water to give the corresponding sulfoxide and sulfone derivatives 10 (i = 1, 2). The double bond in the structures 10 can be reduced by means of catalytic hydrogenation using an appropriate catalyst such as palladium-on-carbon in a suitable solvent such as methanol to give the structures 11. See FIGURES VII, VIII and IX for alternative preparations of thiopyran-4-yl-phenyl-oxazolidinone-5-carboxamides.

DIAGRAM III 89 ΡΕ1478629

DIAGRAM III illustrates the preparation of the piperazinyl-phenyl-oxazolidinone-5-carboxamides 15. The piperizinylphenyl carbamates 12 (see for example J. Med. Chem. 1996, 39 (3), 673-679) may be converted to the oxazolidinone-5-carboxamide 13 using steps similar to those described in DIAGRAM I for the conversion of 1 in 5 using METHOD A. The CBZ protecting group of 13 can be removed by hydrogenation in the presence of a suitable catalyst such as palladium on a carbon or Pearlman catalyst in a solvent such as methanol, ethanol, ethyl acetate or mixtures thereof, and the piperazine ring of 14 can then be acylated or alkylated by methods well known to those skilled in the art to give In the case where R 10 7 represents benzyloxyacetyl, the subsequent catalytic hydrogenation of 15 gives the substituted piperazinyl-phenyl-oxazolidinone-5-carboxamide with hydroxyacetyl 15 (R 10 7 = C (= O) CH 2 OH). Alternatively, the structures 12 may be bis-deprotected using methods known to a person skilled in the art to provide the piperazinyl fluorobenzenamine intermediate which can then be converted into 90 Å structural structures using steps similar to those described in DIAGRAM XII for conversion from 68 to 70.

DIAGRAM IV

DIAGRAM IV illustrates the preparation of 3- and 4-pyridyl and 4-pyranyl-phenyl-oxazolidinone-5-carboxamides 18, 20 and 21. The iodophenyl carbamates 16 (see for example Org. Process Res. Dev. (1), 80-83) can be converted to the 4-iodophenyl-oxazolidinone-5-carboxamide 17 using steps similar to those described in DIAGRAM I for the conversion of 1 in 5 using METHOD B. The aryl iodide 17 may, (see EXAMPLE 7, step 4 below) or 4- (trimethylstannyl) pyridine (See U.S. Patent No. 5 990 136) using a palladium catalyst system such as tris (dibenzylideneacetone ) dipalladium (0) and triphenylarsine in a solvent such as N-methyl-2-pyrrolidinone at a suitable temperature, typically in the range of 50 ° C to 100 ° C, to give the structures 18. The aryl iodide 17 may also can be converted to the arylstannane 19 after treatment with hexamethylditin in the presence of a palladium catalyst such as chlorine of bis (triphenylphosphine) palladium (II) 91 ΡΕ1478629 in a solvent such as 1,4-dioxane at a suitable temperature, typically in the range of from 50øC to 100øC. Coupling of this arylstannane thereafter with the tetrahydro-4 H -pyran-4-one vinyl triflate (See U.S. Patent No. 5,968,962) at room temperature using a catalyst system similar to that used to prepare structures 18 gives the pyranyl-phenyl-oxazolidinone-5-carboxamide 20. Subsequent catalytic hydrogenation provides the structures 21.

DIAGRAM V

DIAGRAM V illustrates the preparation of the thiomorpholinyl-phenyl- and fluorophenyloxazolidinone-5-carboxamides 27. Nitrobenzenes 22 (Ζχο = F, Cl, OTf or other separable group) can be converted into structures 23 after treatment with thiomorpholine in the presence of a base such as N, N-diisopropylethylamine in a suitable solvent such as acetonitrile at a temperature typically in the range of from 25-80 ° C. Reduction of the nitro group of 23 using, for example, catalytic hydrogenation with a suitable catalyst such as Nickel Raney in a suitable solvent system such as a mixture of tetrahydrofuran and water gives the anilines 24 which can be converted into structures 25 using steps similar to those described in DIAGRAM I for the 6-in-4 conversion by METHOD C. Oxidation of the sulfur atom in the structures using the previously described methods (see DIAGRAM II) provides the sulfoxide and sulfone derivatives 26 which are converted into the structures as described in DIAGRAM I.

DIAGRAM VI

(1)

DIAGRAM VI illustrates an alternative preparation of thiomorpholinyl-difluorophenyl-oxazolidinone-5-carboxamide. In this method, phenyl-thiomorpholine sulfone 29 is prepared by treatment of 2,6-difluoroaniline 28 with vinyl sulphone in the presence of aluminum chloride in a suitable solvent such as chlorobenzene at an elevated temperature. Nitration of the phenyl ring of 29 with fuming nitric acid in acetic acid at room temperature then affords the nitrobenzene 30 structure which can then be converted to the aniline 31 as above under catalytic hydrogenation conditions using a suitable catalyst such as like Nickel Raney. Treatment of the aniline 31 with an appropriate alkyl or benzyl chloroformate in the presence of a base such as sodium bicarbonate gives the carbamate structures 32 which can then be converted into the desired structures 33 using steps similar to those described in DIAGRAM I for the conversion of 1 in 5 using METHOD A. Alternatively, the aniline 31 can be converted to 33 using steps similar to those described in DIAGRAM I for the conversion of 6 in 5 using METHOD C.

DIAGRAM VII

DIAGRAM VII illustrates an alternative preparation of the thiopyran-4-ylphenyl-oxazolidinone-5-carboxamides 40. For structures 40 where R2 = H, 4-bromo- or 4-iodoaniline 35 (Z10 = Br, I) may is converted to its isobutyl carbamate derivative 36 (Z1 = Br, I) after treatment with isobutyl chloroformate in the presence of a suitable base such as sodium bicarbonate in a suitable solvent system. Treatment of 36 with two equivalents of n-butyllithium in a suitable solvent such as tetrahydrofuran at a suitable temperature, typically in the range of -78 ° to -40 ° C, gives rise to the dilithiated species resulting from the deprotonation of the carbamate and metal-halogen exchange of the aryl halide. Subsequent treatment with tetrahydro-2H-thiopyran-4-one followed by heating to 0-25øC affords the 4-hydroxythiopyran-4-yl-phenyl-carbamate 37 which can then be reduced to thiopyran-4-ylphenyl -carbamate using, for example, triethylsilane in excess in trifluoroacetic acid at room temperature. The isobutyl carbamate group of 38 is readily cleaved after treatment, for example with aqueous potassium hydroxide in ethylene glycol at an elevated temperature, 100 ° C for example to afford the aniline 39 which can then be converted into the desired structures 40 (R2 = H, i = 1, 2) using steps similar to those outlined in DIAGRAM V for the conversion of 24 to 27. Alternatively, the sulfur atom of carbamate 38 may first be oxidized using the methods described above (DIAGRAM II) to give the corresponding sulfoxide and sulfone derivatives. The carbamate is then cleaved as described above to give aniline S or S, S-dioxide S-oxide 39 which can then be converted to the structures 40 using similar steps 95 ΡΕ1478629 to those described in DIAGRAM I for the 6-fold conversion using METHOD C. Note that the oxidations to give the sulfoxide products provide mixtures of cis and trans isomers which are separable by preparative HPLC. However, there are selective oxidation methods for forming the trans isomer (see Tetrahedron Lett. 2000, 4301-4305, and references cited therein).

With respect to the structures 40 where R2 = H and the other R2 = F, 3-fluoroaniline (Ζ20 = H) can be converted into 4-hydroxythiopyran-4-ylphenyl-carbamate 37 via carbamate 36 (Ζχο = 1, Br), as described in Org. Proc. Res. Dev. 2001, 5, 80-83 and Tetrahedron Lett. 2000, 4301-4305. The carbamate 37 may then be converted to the desired structures 40 (R2, R2 = H, F; i = 1, 2) using the methods described above.

With respect to the structures where R2 = F, the 3,5-difluoroaniline (Zio = H) may be converted into its isobutyl carbamate derivative 36 as described above. Treatment of 36 with two equivalents of n-butyllithium in a suitable solvent such as tetrahydrofuran at a suitable temperature, typically in the range of -78 to -40 ° C, gives rise to the dilithiated species resulting from carbamate deprotonation and maturation in the para position (adjacent to the two fluorine atoms) of the phenyl ring. A chelating additive such as N, N, N ', N'-tetramethylethylenediamine (TMEDA) may be used in this reaction. The next treatment with tetrahydro-2 H -thiopyran-4-one followed by heating to 0-25 ° C affords 4-hydroxythiopyran-4-yl-phenyl-carbamate 37 which can then be reduced to thiopyran-4- ylphenyl carbamate after treatment, for example with excess triethylsilane in trifluoroacetic acid at an elevated temperature, typically from 40 to 75 ° C. The carbamate 38 can then be converted to the desired structures 40 (R2 = F, i = 1, 2) using the methods previously described.

DIAGRAM VIII

DIAGRAM VIII illustrates an additional method for the preparation of the thiopyran-4-ylphenyl-oxazolidinone-5-carboxamide sulfones 43. The tetrahydrothiopyran ring of structures 41 (see DIAGRAM VII for the preparation) may be oxidized using methods previously described The carbamate 42 can then be converted to the desired structures 43 using steps similar to those described in DIAGRAM I for the conversion of 1 in 5 through the intermediate 5-hydroxymethyl-oxazolidinone 2 using METHOD B. 97 ΡΕ1478629

DIAGRAM IX

DIAGRAM IX illustrates an additional method for the preparation of the thiopyran-4-yl-difluorophenyl-oxazolidinone-5-carboxamides 51. The 3,5-difluoroaniline 44 may be protected in the form of its 2,5-dimethylpyrrole derivative 45 after treatment with acetonylacetone and catalytic amounts of p-toluenesulfonic acid in an appropriate solvent, such as mixtures of toluene and tetrahydrofuran, at a suitable temperature, typically from 40øC to reflux. Treatment of n-butyllithium in a solvent such as tetrahydrofuran at a suitable temperature, typically in the range of -78 to -40øC, gives the aryl lithium species resulting from deprotonation at the para position (adjacent to the two fluorine atoms) of the phenyl ring. Subsequent treatment with tetrahydro-2 H -pyrazan-4-one followed by heating to 0-25øC affords 4-hydroxytrypyrane 46 which can be converted to the dihydrothiopyran 47 using, for example, catalytic amounts of p-toluenesulfonic acid in an appropriate solvent such as benzene at an elevated temperature, typically from 60-120 ° C. The pyrrole protecting group may then be removed after treatment with excess hydroxylamine hydrochloride in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as mixtures of ethanol and tetrahydrofuran, at a suitable temperature, typically 40-80Â ° C, to afford the aniline 48 which is reproteated as the carbamate 49 using methods previously described (DIAGRAM VI). The dihydrothiopyran ring of 49 can then be reduced after treatment, for example with excess triethylsilane in trifluoroacetic acid at an elevated temperature, typically from 40-80 ° C, to give the tetrahydrothiopyran 50 which may then be converted to the desired structures 51 (i = 1, 2) using the steps outlined in DIAGRAM VII for conversion from 38 to 40.

DIAGRAM X 99 ΡΕ1478629

DIAGRAM X illustrates the preparation of the N-alkylated benzo-thiazolone and benzoxazolone-oxazolidinone-5-carboxamides 58 (X1 = 0, S, R300 = alkyl or substituted alkyl). For benzothiazolones (X = S), 6-nitro-2-benzothiazolinones 52 (commercially available, known in the literature or prepared using methods known to a person skilled in the art) may be N-alkylated under conditions known to those skilled in the art (see J. Heterocyclic Chem., 1992, 29, 1069, and

U.S. Patent No. 6,069,160, for specific examples of interest), including treatment with an alkylating agent such as iodomethane, dimethylsulfate, iodoethane, 2-iodopropane, bromoacetonitrile or 1-bromo-2-fluoroethane in the presence of a base such as sodium hydride, 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU), or potassium carbonate in a suitable solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or acetone at a suitable temperature, typically from 0 ° C to 100 ° C, to give structures 53 (Xi = S). As regards the 100 ΡΕ1478629 benzoxazolones (Χι = Ο), the 6-nitro-2-benzoxazolones 55 (prepared, for example, from 2-amino-5-nitrophenol 54 according to J. Heterocyclic Chem., 1992, 29, 1069) can be N-alkylated to give 53 (Xi = O) under conditions previously described for benzothiazolinone 52 (see J. Heterocyclic Chem., 1992, 29, 1069; see also

Pharmazie, 1971, 26, 280, and J. Am. Chem. Soc., 1958, 80, 1662, with respect to alternative routes to structures 53 (Xi = 0)). Alternatively, the 2-amino-5-nitrophenols 54 may be reductively alkylated with single aldehydes or ketones, acetone for example in the presence of a suitable reducing agent such as sodium cyanoborohydride in a suitable solvent such as ethanol to give structures 56 which can then be converted into structures 53 (Xi = 0) after treatment, for example with 1,1'-carbonyldiimidazole under conditions similar to those used for the preparation of 55 from 54. Reduction of the nitro group of Using methods known to a person skilled in the art, by means of catalytic hydrogenation, for example, on a suitable catalyst such as palladium-on-carbon or platinum oxide in a suitable solvent system such as mixtures of tetrahydrofuran and methanol (see J. Heterocyclic Chem., 1992, 29, 1069, for example), gives the aniline 57 which can then be converted to structure 58 (X1 = O, S) using steps similar to those described DIAGRAM I for the 6-in-5 conversion by METHOD C.

DIAGRAM XI 101 ΡΕ1478629

DIAGRAM XI illustrates the preparation of indolinyl-oxazolidinone-5-carboxamides 67. The double deprotection of aminoindoline 59 (for the (2R) -methyl derivative, see PCT / US00 / 08224; WOOO / 73301) using methods known to one skilled in the art. for example catalytic hydrogenation over a suitable catalyst such as palladium-on-carbon or Pearlman's catalyst in a suitable solvent affords the aminoindoline 60. The 5-amino group is reprotected as its 2,5-dimethyl-1H pyrrole 61 using the methods described in DIAGRAM IX for the conversion of 44 to 45, and the indoline nitrogen is reprotected as its benzyl carbamate using methods known to a person skilled in the art to give the structures 62. pyrrole protecting group can then be removed using the methods described in DIAGRAM IX for the conversion of 47 into 102 Å and 747862948 to give aminoindoline 63 which is then converted into structures 64 using the steps outlined in DIAGRAM I for the 6-in-4 conversion by METHOD C. The CBZ protection group is then removed and the acylated or alkylated indoline nitrogen using methods known to one skilled in the art to yield 66 using steps similar to those described in DIAGRAM III for conversion 13 to 15, and 66 is then converted to the desired structures 67 as described in DIAGRAM I for the conversion of 4 to 5. Alternatively, aminoindoline 59 may be converted to desired structures 67 using steps similar to those described in DIAGRAM III for the conversion of 12 into 15. DIAGRAM XII

Ο DIAGRAM XII illustrates the preparation of azetidinyl oxazolidinone-5-carboxamides 70. Azetidines 68 (prepared using steps similar to those described in PCT / US96 / 12766) may be selectively acylated on the ring nitrogen using methods known to those skilled in the art to give the structures 69 which can then be converted into the desired structures 70 using steps similar to those described in DIAGRAM I 103 ΡΕ1478629 for the conversion of 6 into 5.

DIAGRAM XIII

DIAGRAM XIII illustrates a general synthesis of thiadiazinone-oxazolidinone-5-carboxamides 77. First, a nitrobenzene carboxylic acid 71 is coupled with a suitable N-protected hydrazine reagent, such as N- (tert-butoxycarbonyl) hydrazine. This reaction can be performed with any number of known coupling reagents, such as HATU or carbodiimides. The coupling reaction is typically carried out in a polar aprotic solvent, such as dimethylformamide, acetonitrile, or mixtures thereof, in the presence of an organic base, such as triethylamine or (N, N-diisopropyl) ethylamine (DIEA). The process is typically carried out at from about 0Â ° C to about 50Â ° C. At 104 ΡΕ1478629 the hydrazide is then converted to the thiohydrazide 73 with a Lawesson's Reagent under conditions with good precedents in the chemical literature. This conversion can be conducted in a suitable organic solvent, such as dioxane or tetrahydrofuran, and is typically carried out at temperatures ranging from about 25øC to about 100øC. By way of example, Lawesson's chemistry is analyzed by Cava et al. in Tetrahedron, 1985, vol. 41, pp. 5061-5087. The next step involves alkylation of the resulting protected thiohydrazide reagent with a suitable alpha-substituted ester reagent (such as methyl or ethyl ester) to give structures 74. The ester carries a

easily separable at the alpha position relative to the ester functionality, e.g., bromo, iodo, nitrobenzenesulfonyloxy, mesyloxy (OMs), or a like group. The reaction is typically carried out in a polar organic solvent such as acetonitrile, tetrahydrofuran, or dimethylformamide in the presence of an organic or inorganic base, such as potassium carbonate, pyridine, or triethylamine. A typical temperature range for this transformation is from about 0 ° C to about 50 ° C. The next step involves deprotection of an acid sensitive thiohydrazide protecting group (exemplified by Boc in this case). Under reaction conditions, acid-induced N-deprotection is immediately followed by high yield heterocyclisation on the desired thiadiazinone derivative 75. This transformation is conveniently carried out in the presence of organic or inorganic acids such as trifluoroacetic acid or hydrogen chloride . The reaction is carried out in an organic solvent, such as dichloromethane, dichloroethane, dioxane, or tetrahydrofuran, at temperatures ranging from about 10Â ° C to about 60Â ° C. The nitro group is then reduced using methods known to one skilled in the art to give the aniline 76. This reduction can be achieved by reaction of the nitro intermediate with metal iron. The reaction is carried out at temperatures between 60 ° C and 90 ° C in mixtures of water and alcohol (methanol, ethanol, etc.) as solvent, and in the presence of ammonium chloride to buffer the reaction mixture. The aniline is then converted to the desired structures using steps similar to those described in DIAGRAM I for the conversion of 6 into 5.

DIAGRAM XIV

Synthesis of dihydropyridones has good precedents in the prior art. Thus, dihydropyridone compounds can be made by means of variations of oxidative transformations of piperidone derivatives exemplified by the following references: Stutz et al. in 106 ΡΕ1478629

Tetrahedron Lett., 1973, pp. 5095-5098; Dodd et al., Tetrahedron Lett., 1991, pp. 3643-3646; Evans et al., Tetrahedron Lett., 1995, pp. 3985-3988; Blache et al., Heterocycles, 1997, pp. 57-69; and Ishii et al., Tetrahedron

Lett., 1997, pp. 7565-7568. In another embodiment, dihydropyridone compounds can be synthesized by means of variations of Diels-Alder hetero-transformations of imine derivatives exemplified by the following publications: Diez et al., Heterocycles, 1990, p. 485; Waldmann et al., Tetrahedron, 1993, pp. 397-416; Lock et al., Tetrahedron Lett., 1996, pp. 2753-2756; Kirschbaum et al., Tetrahedron Lett., 1997, pp. 2829-2832; Kirschbaum et al., Chem. Eur. J., 1997, pp. 143-151; and Kirschbaum et al., J. Org. Chem, 1998, pp. In still another embodiment, dihydropyridone compounds can be prepared by reductive transformations of pyridine and pyridone derivatives, see, e.g., references: Haider, et. al., Helv. Chim. Acta, 1975, p. 1287; Guerry et al., Synthesis, 1984, p. 485; Guerry et al., Chimia, 1987, p. 341; Comins et al., Heterocycles, 1994, pp. 1121-1140; and Dehmlow et al.

Heterocycles, 1994, pp. 355-366. DIAGRAM XIV illustrates a general method for the preparation of dihydropyridone oxazolidinone-5-carboxamides from nitrobenzene and piperidine derivatives. Step 1 involves a nucleophilic aromatic substitution reaction of a suitable nitrobenzene with a piperidine derivative, such as 4-piperidone, to give structures 79. This reaction 107 ΡΕ 1477729 is performed in a polar aprotic solvent such as dimethylformamide, acetonitrile, or dimethylsulfoxide in the presence of an organic or inorganic base, such as pyridine, triethylamine, or potassium carbonate. Temperatures in the range of about 20øC to about 80øC are generally suitable for this reaction. The next step involves the formation of a silyl enolate 80 from the 1-arylpiperidone intermediate 79 and a silylating agent, such as triisopropylsilyl chloride, trialkylsilyl triflate, or a like reagent. This reaction is typically conducted in the presence of an organic base, such as triethylamine, pyridine, or imidazole at temperatures of from about 0øC to about 60øC. Step 3 of this synthesis involves oxidation of the silyl enolate intermediates to the dihydropyridone compounds 81 with a suitable inorganic oxidant such as ceric ammonium nitrate (CAN, described by Evans et al in Tetrahedron Lett., 1995, Vol. 36, pp. 3985-3988) or palladium acetate (as described by Comins et al in Tetrahedron Lett., 1995, vol 36, pp. 9449-9452). The nitro group of 81 can then be reduced using methods known to a person skilled in the art, for example by reduction with iron metal (see DIAGRAM XIII) or by catalytic hydrogenation on pad / CaCO 3 in the presence of acid acetic acid to give the aniline 82 which is then converted to the desired structures 83 (Wi0 = O) using steps similar to those described in DIAGRAM I for the conversion of 6 to 5. The oxime derivatives of 83 can thereafter , be prepared using methods known to one skilled in the art. The single oxime (W0 = N (OH)) may be prepared from after treatment with hydroxylamine hydrochloride in the presence of a suitable base such as pyridine which may also be used as solvent or as part of a solvent mixture.

DIAGRAM XV

DIAGRAM XV illustrates the preparation of benzoxazin-3-one, benzothiazin-3-one and tetrahydroquinolin-2-one oxazolidinone-5-carboxamides 88. Structures 84 (Z5 = O, S, CH2, etc.), which are known in the literature (see W099 / 37641 and WO99 / 40094 and references cited therein for specific examples) or may be prepared using known methods (such as nitration of the parent bicyclic ring system), can be alkylated using methods previously described (see DIAGRAM X ) to give 85. The nitro group is then reduced using methods known to a person skilled in the art, for example by reduction with iron metal (see 109 ΡΕ1478629 DIAGRAM XIII) or by catalytic hydrogenation, in order to to give the aniline 86 which can then be converted to the desired structures 88 (Vi = O) using steps similar to those described in DIAGRAM I for the conversion of 6 to 5. In addition, the thioxo derivatives (Vi = S) may be prepared from intermediate structures 87 (Vi = 0). Treatment of 87 (Vi = 0) with Lawesson's Reagent under conditions with good precedents in the literature (see DIAGRAM XIII) provides the thioxo 87 (Vi = S) intermediates which may and then converted into the desired structures 88 (Vi = S), as previously described.

DIAGRAM XVI

DIAGRAM XVI illustrates general methods for the preparation of the thiopyran-sulphoximine oxazolidinone-5-carboxamides 95. The sulfoxide structures 89 in the cis and trans configuration 110 are prepared as outlined in DIAGRAM VII or using methods similar to those described in Patent No. 6,239,283) can be converted to sulfoximine 90 with stereochemistry retention of the sulfoxide using amination methods known to a person skilled in the art, for example by treatment with O-mesitylenesulfonylhydroxylamine (MSH) in a suitable solvent such as as methylene chloride generally at or near room temperature (see also WOO1 / 46185 and Synthesis, 2000, I, 1). The sulfoximines 90 can then be converted to the desired structures 95 (R 315 = H) using steps similar to those described in DIAGRAM VII for the conversion of 38 into 39 followed by those in DIAGRAM I for the conversion of 6 to 5. Sulfoximines 90 may also be alkylated to give structures 91 (where R 315 represents alkyl or substituted alkyl), for example by reaction with an aldehyde or ketone, triethylsilane and trifluoroacetic acid in a suitable solvent such as acetonitrile at a temperature, depending on the solvents, in the solvent. ranging from 10-120øC or by reaction with an aldehyde or ketone and formic acid using Leuckart-Wallach or Eschweiler-Clarke conditions. Para-formaldehyde is a convenient source of formaldehyde for this reaction to provide the N-methyl derivatives (see WOO1 / 46185 for additional methods for the functionalization of the sulfoximine group). The substituted sulfoximines 91 may then be converted into the desired structures 95, as previously described. Alternatively, the alkylation may be carried out as the last step in the sequence using structures 95 (R 31 = H). The amination may also be carried out at a later stage in the synthesis starting from the sulfoxide structures 92. These structures may be prepared from the carbamates 89 as described above or using the methods outlined in DIAGRAM VII. The amination of 92 under the conditions previously described provides the sulphoximins 93 which can then be converted into the desired structures 95 (R315 = H) as above. The sulphoximine group may also be functionalized as described above.

The corresponding thiomorpholine sulphoximine derivatives where the thiopyran ring at 95 is replaced by the thiomorpholine ring can be prepared using steps similar to those described above. However, the amination is generally carried out using sodium azide in polyphosphoric acid at a temperature generally in the range of from about 40 ° C to about 70 ° C.

DIAGRAM XVII

DIAGRAM XVII illustrates a method for the preparation of the dihydrothiazinylsulphone-oxazolidinone-5-one of the carboxamides 98. The thiomorpholine-S, S-dioxide-oxazolidinone-5-carboxamides 96 (see DIAGRAM V) can be converted into the derivatives dihydrothiazole 97 after treatment with a suitable organic oxidant such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or chloranil. This transformation is typically carried out in a polar organic solvent, such as dioxane, tetrahydrofuran or dimethylacetamide, at a temperature in the range of about 60øC to about 110øC. The structures 97 may then be converted to the desired structures, as previously described in DIAGRAM I.

DIAGRAM XVIII

DIAGRAM XVIII illustrates a method for the preparation of the tetrahydropyridyl- or piperidinyl-oxazo-linoono-5-carboxamides 102. The tetrahydropyrimyl aniline derivatives 99 (See WO 97/09328 or WO 99/64417) may be converted to the tetrahydropyridyl oxazolidinone derivatives 100 by Method C described above with respect to 113 ΡΕ1478629 to Diagram 1. Removal of the protecting group (Z12 = Cbz, BOC, or Bn) using known methods provides the deprotected derivatives 101. The conservation of the double bond in the tetrahydropyridyl group can be achieved by removal of Cbz with a treatment of TMSI followed by methanol, BOC with a treatment of TFA, or Bn with a treatment of α-chloroethyl chloroformate followed by MeOH. Cleavage of the protecting group under catalytic hydrogenation conditions results in the reduction of the double bond to give the piperidinyl structure 101. The functionalization of the tetrahydropyridyl or piperidinyl nitrogen can be carried out by known methods, such as by means of alkylation and acylation. (See also WO 99/64417, W002 / 096916, and W001 / 40236)

Suitable intermediates useful in the preparation of compounds of this invention and additional synthetic methods to aid in the production of the compounds can be found, for example, in the following publications.

U.S. Pat. 5,225,565; 5,181,403; 5,164,510; 5,247,090; 5,231,188; 5,565,571; 5,547,950; 5,529,998; 5,627,181; 5,843,976; 5,861,413; 5,827,857; 5,869,659; 5,952,324; 5,968,962; 5,688,792; 6 069 160; 6,239,152; 5,792,765; 4,705,799; 5,043,443; 5,652,238; 5,827,857; 5,529,998; 5,684,023; 5,627,181; 5,698,574; 6,156,056; 6,194,441; 6,110,936; 6,069,149; 6,271,383; 5,981,58; 6,051,716; 6,043,266; 6,383,307; 5,614,535; 6,239,283; 5,990,136; and 5,523,403. 114 ΡΕ1478629

PCT Applications and Publications PCT / US93 / 04850 WO 94/01110; PCT / US94 / 08904, WO95 / 07271; PCT / US95 / 02972 WO95 / 25106; PCT / US95 / 10992, WO96 / 13502; PCT / US96 / 05202 WO 96/35691; PCT / US96 / 12766, WO97 / 09328; PCT / US96 / 13726 WO 97/10235; PCT / US96 / 14135, W09 7/10223; PCT / US96 / 17120 WO97 / 19089; PCT / US96 / 19149, WO97 / 21708; PCT / US97 / 01970 WO97 / 30981; PCT / US95 / 12751, WO96 / 15130, PCT / US96 / 00718 W096 / 23788, W098 / 54161, W099 / 29688, WO99 / 03846, W099 / 37641 W099 / 37652, W099 / 40094, WO97 / 30995, WO97 / 09328, W001 / 81350 W001 / 40236, WO00 / 21960 W001 / 04022, WO00 / 73301, WOO1 / 46185 W099 / 64417, WO02 / 59155, W002 / 096916 and WO95 / 07271.

EXAMPLES

Without further elaboration, we believe that one skilled in the art may, using the foregoing description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and / or carry out the various processes of the invention and are intended as merely illustrative, and not limitations of the foregoing presentation in any way whatsoever. Those skilled in the art will readily recognize the appropriate variations from the procedures both as to the reagents and the conditions and techniques of the reactions. EXAMPLE 1 (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-

oxo-5-oxazolidinecarboxamide - Method A ΔΕ1478629 115

Or

Step 1: Preparation of (5R) - (-) - 3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid

A solution of benzyl 3-fluoro-4- (4-morpholinyl) phenylcarbamate (J. Med. Chem. 1996, 39 (3), 673-679, 2.50 g, 7.57 mmol) in tetrahydrofuran (37.8 mL) at -78 ° C under nitrogen is treated with n-butyllithium (1.6M in hexanes, 4.82 mL, 7.72 mmol) dropwise and stirred at -78 ° C for 30 minutes. The cooling bath is removed and the mixture is allowed to warm slowly to -40øC, at which point potassium (2R) -glycidate (J. Org. Chem. 1992, 57 (12), 3380-3387, 974 mg, 7.72 mmol). After subsequent heating to room temperature, the resulting mixture is vigorously stirred for 2.75 days and then quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (20 mL) and extracted with ethyl acetate (2 x 75 mL) to remove the starting remainder. The aqueous phase is adjusted to pH 2 with 1 M aqueous hydrochloric acid, saturated sodium chloride and extracted with methylene chloride (5 x 100 mL), and this combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure of to give rise to the gross product. The product mixture is then chromatographed on a flash 40 M silica gel cartridge (90 g, 32-63 Âμm), eluting with a gradient of 116 Âμl and 147.79 acetonitrile / methylene chloride (10/90-40 / 60) containing 1% formic acid, and the fractions with a Rf = 0.15 per TLC (acetonitrile / methylene chloride, 50/50 + 1% formic acid) are pooled and concentrated to give the title compound, 1H NMR (400 MHz, DMSO-d 6) δ 13.7 (s I-1> 1H), 7.48 (dd, 1H), 7.23 (m, 1H), 7.05 (t, 1H), 5.17 (dd, 1H), 4.30 (t, 1H), 4.06 (dd, 1H), 3.73 (m, 4H), 2.96 (m, 4H); MS (ESI +) for C 14 H 15 FN 2 O 5 m / z 311 (M + H) +; [Î ±] 25D = -38Â ° (c 0.94, DMSO).

Step 2: Preparation of (5R) - (-) - 3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide To a flame dried flask containing (5R) - (-) - 3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid (Step 1, 250 mg, 0.806 mmol) under nitrogen is added oxalyl chloride (4 mL) with stirring. The flask is capped with a drying tube, and the mixture is stirred at room temperature for 15 h, then concentrated under reduced pressure to give the intermediate [MS (ESI +) m / z 325 (M + H) + observed relative to the methyl ester obtained by reaction of the acid chloride with methanol] which is used without further purification. This intermediate is then taken up in anhydrous tetrahydrofuran (8 mL) under nitrogen, cooled to 0 ° C, and bubbled into ammonia (g) for 5 minutes. The resulting mixture is capped with a drying tube, stirred at room temperature for 1 h, and then diluted with water (20 mL) and extracted with methanol / chloroform (10/90, 2 x 30 mL). The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the product mixture is recrystallized from ethyl acetate / hexane to give the title compound, mp 185-187øC ( decomp.); MS (ESI +) for C 14 H 16 FN 3 O 4 / z 310 (M + H) +; [Î ±] 25D = -230 (c 0.89, DMSO). EXAMPLE 2 (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-methyl-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 1, Step 2, and making non-basic variations but replacing ammonia with methylamine, the title compound is obtained, mp 182-183 ° C (decomp.); MS (ESI +) for C 15 H 18 FN 3 O 4 m / z 324 (M + H) +; [Î ±] 25d = -39Â ° (c 0.92, DMSO). EXAMPLE 3 (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -Di-1-oxo-5-oxazolidinecarboxamide

To a flask is dried over flask under nitrogen, allylamine (0.60 mL, 8.05 mmol) is added. The flask is cooled in an ice bath, and a solution of 118 Ρ E1478629 (5R) -3- [3- fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarbonyl chloride (EXAMPLE 1, Step 2, 0.805 mmol in theory) in anhydrous tetrahydrofuran (8.0 mL) The resulting mixture is stirred (10 mL) and extracted with methylene chloride (20 mL) .The organic phase is washed with water (10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness ) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel cartridge (40 g, 32-63 μl), eluting with a gradient Combination of the fractions with a Rf = 0.44 by TLC (methanol / chloroform, 5/95) affords the title compound as a white solid. , pf 167-169 ° C; MS (ESI +) for C 17 H 20 FN 3 O 4 m / z 350 (M + H) +; [Î ±] 25D = -44Â ° (c 0.94, DMSO). EXAMPLE 4 (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-propyl-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 3, and making non-basic variations, but replacing allylamine with propylamine and triturating and filtering the final product from methanol / diethyl ether, the title compound is obtained, mp 165-167øC; MS (ESI +) for 119 Ρε1478629 C17H22FN3O4 m / z 352 (M + H) +; [Î ±] 25D = -403 (c 1.02, DMSO). EXAMPLE 5 (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-methoxy-2-oxo-5-oxazolidinecarboxamide

A mixture of (5R) - (-) - 3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 1, Step 1, 150 mg, 0.483 mmol) and (61 mg, 0.724 mmol) in tetrahydrofuran / water (1/1, 4.8 mL) is treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (278 mg and the resulting mixture is stirred at room temperature for 30 minutes and is then diluted with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase is washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel cartridge (40 g , 32-63 μιη),

eluting with methanol / methylene chloride (2.5 / 97.5). Combination of the fractions with a Rf = 0.53 by TLC (methanol / chloroform, 10/90) gives the title compound, mp 206-208 ° C (decomp.); MS (ESI +) for C 15 H 18 FN 3 O 5 m / z 340 (M + H) +; [Î ±] 25D = -56Â ° (c 0.92, DMSO). EXAMPLE 6 (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-hydroxy-2-oxo-5-oxazolidinecarboxamide 120 ΡΕ1478629

Step 1: Preparation of (5R) - (-) - 3- [3-fluoro-4- (4-morpholinyl) phenyl] -N-benzyloxy-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 5, and making non-basic variations, but substituting O-methylhydroxylamine hydrochloride for 0-benzylhydroxylamine hydrochloride, the title compound is obtained, mp 191-193 ° C (decomp. ); MS (ESI +) for C 21 H 22 FN 3 O 5 m / z 416 (M + H) +; [Î ±] 25D = -460 (C 0.93, DMSO).

Step 2: Preparation of (5R) - (-) - 3- [3-fluoro-4- (4-morpholinyl) phenyl] -N-hydroxy-2-oxo-5-oxazolidinecarboxamide To a mixture of (5R) 3- (3-fluoro-4- (4-morpholinyl) phenyl] -N-benzyloxy-2-oxo-5-oxazolidinecarboxamide (Step 1, 300 mg, 0.722 mmol) in methanol (28: 8 mL) is added 5% palladium-on-carbon (77 mg) under nitrogen. The resulting mixture is degassed and stirred under a hydrogen atmosphere (flask) for 1 h. The catalyst is then removed by filtration through Celite, rinsing with methanol (60 mL), and the filtrate is concentrated under reduced pressure. Trituration of this residue with (5% methanol / methylene chloride) / diethyl ether gives the title compound, mp 141-143 ° C; MS (ESI +) for 121 Ρε1478629 C14H16FN3O5 m / z 326 (M + H) +; [Î ±] 25D = -70Â ° (c 0.99, DMSO). EXAMPLE 7 (5R) - (-) - 3- [4- (3-Pyridyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (5R) - (-) - 3- [3-fluoro-4-iodophenyl] -5-hydroxymethyl-2-oxazolidinone

A solution of isobutyl 3-fluoro-4-iodophenylcarbamate (Org. Process Res. Dev. 2001, 5 (1), 80-83, 5.00 g, 14.83 mmol) in dry tetrahydrofuran (59 mL) at -78 ° C under nitrogen is treated with lithium hexamethyldisilazide (1.0M in tetrahydrofuran, 15.6 mL, 15.57 mmol) dropwise and stirred at -78 ° C for 45 minutes. Then, glycidyl (R) -butyrate (2.21 mL, 15.57 mmol) is added dropwise, and the resulting mixture is stirred at -78 ° C for 1 h and at room temperature for 2.75 days. The reaction mixture is then quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (20 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (25 mL), and the combined organic phase is washed with water (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product mixture is then chromatographed on a Cartridge Flash 40M silica gel (90 g, 32-63 μl), eluting with a gradient of methanol / methylene chloride (1 / 99-2 / 98), and fractions with a Rf = 0.25 by TLC (methanol / chloroform, 5/95) are pooled and concentrated to give the title compound, mp 116-117 ° C; MS (ESI +) for C10 H9 FINO3 m / z 338 (M + H) +; [Î ±] 25D = -41 (c 0.98, DMSO).

Step 2: Preparation of methyl (-) - (5R) -3- [3-fluoro-4-iodophenyl] -2-oxo-5-oxazolidinecarboxylate

A solution of (5R) - (-) - 3- [3-fluoro-4-iodoffenyl] -5-hydroxymethyl-2-oxazolidinone (Step 1, 7.61 g, 22.58 mmol) in acetone ml) at -10 ° C is treated with a mixture of CrCl 3 (6.21 g, 62.1 mmol) in sulfuric acid (6M, 16.9 mL, 101 mmol) dropwise over 15 minutes. The resulting mixture is allowed to slowly warm to room temperature with vigorous stirring (slight exotherm to 35øC) and is stirred for an additional period of 16 h. The mixture is then treated with isopropanol (35 mL), diluted with brine (150 mL) and diethyl ether (150 mL), stirred until all solids are dissolved, and the layers are separated. The aqueous phase is extracted with diethyl ether (100 mL), and the combined organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude carboxylic acid intermediate which is taken up in methanol (225 mL) and treated with concentrated sulfuric acid (8 drops). The resulting homogeneous mixture is stirred at room temperature for a period of 20 h and then concentrated under reduced pressure to give the crude methyl ester which is chromatographed on two 40 M Flash 40M silica gel cartridges (32 -63 μπι), eluting with a gradient of ethyl acetate / heptane (20 / 80-40 / 60). Combination of the fractions with a Rf = 0.36 by TLC (ethyl acetate / hexane, 50/50) gives the title compound, mp 106-109øC; MS (ESI +) for C 19 H 9 FNO 4 m / z 366 (M + H) +; [Î ±] 25d = -30 (c 0.93, DMSO).

Step 3: Preparation of (5R) - (-) - 3- [3-fluoro-4-iodophenyl] -2-oxo-5-oxazolidinecarboxamide D = -19 (c 0.97, DMSO).

A solution of methyl (-) - (5R) -3- [3-fluoro-4-iodophenyl] -2-oxo-5-oxazolidinecarboxylate (Step 2, 6.23 g, 17.1 mmol) in acetonitrile mL) is treated with concentrated ammonium hydroxide (85 mL), and the resulting mixture is stirred at room temperature for 1 h. The mixture is then diluted with brine (100 mL) and extracted with methylene chloride (3 x 100 mL), and the combined organic phase is washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is diluted with hot ethyl acetate (200 mL) and filtered to remove inorganic residue, and the filtrate is diluted with hexanes (300 mL). The resulting precipitate is isolated by filtration to give the title compound, mp 176-178 ° C; MS (ESI +) for C 10 H 9 FN 2 O 3 m / z 351 (M + H) +; [a] 124 ΡΕ1478629

Step 4: Preparation of 3- (trimethylstannyl) pyridine

A mixture of hexamethyldistane (654 mg, 1.99 mmol), 3-bromopyridine (300 mg, 1.90 mmol) and bis (triphenylphosphine) palladium (II) chloride (40 mg, 0.057 mmol) in 1,4-dioxane (9.5 ml) is degassed, heated to 90øC under nitrogen, stirred at this temperature for 2.5 h at room temperature overnight, and is then concentrated under reduced pressure. The product mixture is chromatographed on a 40 g Flash 40S silica gel cartridge (32-63 μl), eluting with ethyl acetate / heptane (20/80), and fractions with a Rf = 0.47 by TLC (50/50 ethyl acetate / hexane) are pooled and concentrated to give the title compound (see Chem., Pharm Bul, 1982, 30 (5), 1731-1737 for characterization).

Step 5: Preparation of (5R) - (-) - 3- [4- (3-pyridyl) -3-fluoro-phenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of (5R) - (-) - 3- [3-fluoro-4-iodophenyl] -2-oxo-5-oxazolidinecarboxamide (Step 3, 422 mg, 1.21 mmol), 3- (trimethylstannyl) pyridine (22 mg, 0.0242 mmol), triphenylarsine (59 mg, 0.194 mmol) and copper (I) iodide (9 mg, 0.25 mmol) , 0484 mmol) in N-methyl-2-pyrrolidinone (4.8 mL) under nitrogen is degassed, warmed to 50 ° C and stirred at this temperature for 2 days, during which more tris (dibenzylideneacetone) dipalladium ( 0) (22 mg, 0.0242 mmol), triphenylarsine (59 mg, 0.194 mmol) and 125 ΡΕ1478629 copper (I) iodide (9 mg, 0.0484 mmol). The resulting mixture is diluted with water (15 mL) and extracted with methylene chloride (3 x 20 mL), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil is diluted with ethyl acetate (25 mL) and extracted with aqueous hydrochloric acid (1M, 25 mL), and the aqueous phase is neutralized with sodium hydroxide (s), saturated with sodium chloride and extracted with methylene chloride (3 x 25 mL) containing a small amount of methanol. This combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate / hexane to give the title compound, mp 240-242 ° C (dec. ); MS (ESI +) for C 15 H 12 FN 3 O 3 m / z 302 (M + H) +; [Î ±] 25d = -25 (c 0.94, DMSO). EXAMPLE 8 (5R) - (-) - 3- [4- (4-Pyridyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 7, Step 5, and making non-basic variations, but substituting 4- (trimethylstannyl) pyridine for 3- (trimethylstannyl) pyridine (US 5 990 136; November 23, 1999), the title compound is obtained. (dec.), mp 256-259 ° C (dec.); MS (ESI +) for C15H12FN3O3 126 ΡΕ1478629 m / z 302 (Μ + Η) [a] 25D = -27 (c 0.94, DMSO). EXAMPLE 9 (5R) - (-) - 3- [4- (3,6-Dihydro-2 H -pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (5R) -3- [4- (trimethylstannyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of (5R) - (-) - 3- [3-fluoro-4-iodophenyl] -2-oxo-5-oxazolidinecarboxamide (EXAMPLE 7, Step 3, 3.50 g, 10.0 mmol), hexamethylditin 3.44 g, 10.5 mmol) and bis (triphenylphosphine) palladium (II) chloride (140 mg, 0.200

mmol) in 1,4-dioxane (50 mL) under nitrogen is degassed, heated to 90 ° C and stirred at 90 ° C for 2 h and at room temperature overnight. The resulting mixture is concentrated under reduced pressure to remove dioxane, diluted with methylene chloride (75 mL), washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a Flash 40M cartridge of 90 g silica gel (32-63 μl), eluting with a meta-nol / methylene chloride gradient (1 / 99-2 / 98), and the fractions with a Rf = 0.26 by TLC (methanol / chloroform, 5/95) are pooled and concentrated to give the title compound, 1H NMR Î'-147.7929 NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7 (S, 1H), 5.00 (dd, 1H), 4.26 (m, 2H), 0.35 (m, 9H) ).

Step 2: Preparation of (5R) - (-) - 3- [4- (3,6-dihydro-2 H -pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of 3,6-dihydro-2 H -pyran-4-yl trifluoromethanesulfonic acid ester (US 5 968 962,

(54 mg, 0.0588 mmol) and triphenylserine (144 mg, 0.470 mmol) in N-methyl-2-nitrobenzaldehyde pyrrolidinone (14.7 mL) is degasified and stirred under nitrogen for 5 minutes. Then (5R) -3- [4- (trimethylstannyl) -3-fluorophenyl) -2-oxo-5-oxazolidinecarboxamide (Step 1, 1.14 g, 2.94 mmol) is added, and the resulting mixture is stirred at room temperature for 5 days. The reaction mixture is then diluted with water (25 mL) and extracted with ethyl acetate (3 x 30 mL), and the combined organic phase is washed with water (3 x 30 mL) and brine (20 mL) ), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product mixture is chromatographed on a Flash 40M cartilage of 90 g silica gel (32-63 μl), eluting with a methanol / methylene chloride gradient, (1 / 99-2.5 / 97.5) , and the fractions with a Rf = 0.40 by TLC (methanol / chloroform, 2x5/95) are pooled and concentrated to give the title compound, mp 164-169 ° C; MS (ESI-) for C 15 H 15 N 2 O 4 F m / z 305 (M-H); [Î ±] 25D = -23 (c 0.96, DMSO). EXAMPLE 10 (5R) - (-) - 3- [4- (Tetrahydro-2H-pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of (5R) - (-) - 3- [4- (3,6-dihydro-2 H -pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide (EXAMPLE 9, Step 2, 200 mg, 0.653 mmol) and 10% palladium on carbon (139 mg, 0.131 mmol) in methanol (26 mL) is shaken under a 40 psi hydrogen atmosphere in a Parr apparatus for 5 h. The catalyst is then removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure and chromatographed on a flash cartridge of 40 g of silica gel (32-63 μl), eluting with a gradient of methanol / methylene chloride (2 / 98-3 / 97). Combination of the fractions with a Rf = 0.37 by TLC (methanol / chloroform, 2x5/95) gives the title compound, mp 153-156øC; MS (ESI-) for C 15 H 17 N 2 O 4 F m / z 307 (Μ-α, [α] 25D = -21 (c 0.87, DMSO). EXAMPLE 11 (5R) -3- [4- 6-dihydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide 129 ΡΕ1478629

Step 1: Preparation of (-) - (5R) -3- [4- (3,6-dihydro-2-thiazol-4-yl) -3-fluorophenyl] -2-oxo-5- oxazolidinecarboxylate

Following the general procedure of EXAMPLE 1, Step 1, and making non-basic variations, but substituting benzyl 3-fluoro-4- (4-morpholinyl) phenylcarbamate for 4- (3,6-dihydro-2H-thiopyran-4 -yl) -3-fluorophenylcarbamate (WO 00/44741, 3 August 2000), the crude intermediate (5R) -3- [4- (3,6-dihydro-2'-thiopyran- 4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxylic acid and is used without further purification. This intermediate (crude 540 mg) is taken up in methanol (16 mL), a drop of concentrated sulfuric acid is added, and the mixture is stirred at room temperature for 21 h. Then the reaction mixture is concentrated under reduced pressure and chromatographed on a Flash 40S Cartilage of 40 g of silica gel (32-63, μιη), eluting with ethyl acetate / heptane (25/75). Fractionation and concentration of the fractions with a Rf = 0.25 by TLC (ethyl acetate / hexanes, 50/50) gave the title compound, mp 106-110 ° C; MS (ESI +) for C 16 H 16 NO 4 FS m / z 338 (M + H) +; [Î ±] 25D = -36 (c 0.99, DMSO). 130 ΡΕ1478629

Step 2: Preparation of (5R) - (-) - 3- [4- (3,6-dihydro-2H-thio-pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 7, Step 3, and making non-basic variations, but substituting methyl (-) - (5R) -3- [3-fluoro-4-iodophenyl] -2-oxo-5-oxazolidinecarboxylate methyl (-) - (5R) -3- [4- (3,6-dihydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1) and purifying the product by recrystallization from methanol / diethyl ether, the title compound is obtained, mp 182-184 ° C (dec.); MS (ESI-) for CbsH 3 FNOSO: m / z 321 (M-H); [Î ±] 25D = -24 (c 0.93, DMSO).

Step 3: Preparation of (5R) -3- [4- (3,6-dihydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide S-Oxide

A mixture of (5R) - (-) - 3- [4- (3,6-dihydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide 2, 294 mg, 0.912 mmol) in methanol (18 mL) is treated with sodium periodate (205 mg, 0.958 mmol) in water (3.8 mL), and the mixture is stirred at room temperature for 44 h. The resulting mixture is diluted with water (25 mL) and extracted with methylene chloride (5 x 30 mL), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product mixture is triturated with acetone / diethyl ether and then filtered to give the title compound 131 ΡΕ1478629

as a mixture of two diastereomers, 1 H NMR (400 MHz, DMSOd 6) δ 7.87 (s, 1H),, 7.63 (s, br, t), 7.52 (d, 1H), (M, 1H), 4.09 (m, 2H), 5.83 (m, 1H), 5.04 (dd, 1H), 4.29 (t 1H) 1H), 3.39 (m, 1H), 3.10 (m

1H), 2.92 (m, 2H), 2.54 (m, 1H); MS (ESI +) for C 15 H 15 FN 2 O 4 S m / z 339 (M + H) +. EXAMPLE 12 (5R) - (-) - 3- [4- (3,6-dihydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5- oxazolidinecarboxamide

A solution of (5R) - (-) - 3- [4- (3,6-dihydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide (EXAMPLE 11, Step 2, 209 mg, 0.648 mmol) in water / acetone (25/75, 13 mL) under nitrogen is treated with N-methylmorpholine N-oxide (190 mg, 1.62 mmol) and tetroxide (2.5 wt% in tBuOH, 0.41 mL, 0.0324 mmol), and the mixture is stirred at room temperature for 43 h. The reaction is then treated with 1/2-saturated aqueous sodium bisulfite (25 mL) and extracted with methylene chloride (3 x 25 mL), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. reduced pressure. The residue is chromatographed on a Flash 40S Cartilage of 40 g of silica gel (32-63 μl), eluting with a gradient of methanol / methylene chloride (2.5 / 97.5-132 ΡΕ1478629 4/96), and the fractions with a Rf = 0.48 by TLC (methanol / chloroform, 10/90) are pooled and concentrated to give the title compound, mp 206-208 ° C; MS (ESI-) for C 15 H 15 FN 2 O 5 S m / z 353 (M-H); [Î ±] 25D = -20 (c 0.98, DMSO). EXAMPLE 13 (5R) - (-) - 3- [4- (tetrahydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of (5R) - (-) - 3- [4- (3,6-dihydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5 (44 mg, 0.0412 mmol) in methanol (21 mL) is shaken under an atmosphere of 40 psi of hydrogen in an apparatus of Parr for 16 h. The catalyst is then removed by filtration through a pad of Celite, rinsing with methanol and tetrahydrofuran, and the filtrate is concentrated under reduced pressure and triturated with (5% methanol / methylene chloride) / ether diethyl ether. Filtration then affords the title compound, mp 229-231 ° C (dec.); MS (ESI-) for CysH 3 FN 2 O 3 S m / z 355 (-) -; [α] 25d = -20 (c 0.83, DMSO). EXAMPLE 14 (5R) - (-) - 3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinecarboxamide 133 ΡΕ1478629

Step 1: Preparation of phenylmethyl (-) - 4- [4 - [(5R) -5- (aminocarbonyl) -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylate

Following the general procedure of EXAMPLE 1, Step 1, and making non-basic variations, but substituting benzyl 3-fluoro-4- (4-morpholinyl) phenylcarbamate for 4- (4 - {[benzyloxycarbonyl] amino} -2-fluorophenyl) -1-piperazinecarboxylate (J. Med. Chem. 1996, 39 (3), 673-679), the crude intermediate 4- [4 - [(5R) -5-carboxy-2-oxo-3- oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylate [MS (ESI-) for C 22 H 22 N 3 O 6 m / z 442 (MH) '] and is used without further purification. This intermediate (1.66 g crude) is taken up in methanol (75 ml), 4 drops of concentrated sulfuric acid is added, and the mixture is stirred at room temperature for 19 h. The reaction mixture is then concentrated under reduced pressure and chromatographed twice on a Flash 40M cartridge of 90 g silica gel (32-63 μl), eluting with a gradient of methanol / methylene chloride (1 / 99- 2/98). Combining and fractionating the fractions with a Rf = 0.64 by TLC (methanol / chloroform, 5/95) provided 740 134 Ρ AND 147.7929 mg of the intermediate 4- [2-fluoro-4 - [(5R) -5- (methoxycarbonyl) -2-oxo-3-oxazolidinyl] phenyl] -1-piperazinecarboxylate [MS (ESI +) for C 23 H 24 N 3 O 6 F m / z 458 (M + H) +; 75-80% purity] which is used without further purification. This intermediate is taken up in 2M ammonia in methanol (13 mL), and the resulting mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue is chromatographed on a Flash 40M cartridge of 90 g silica gel (32-63 μl), eluting with a methanol / methylene chloride gradient (1 / 99-3 / 97), and the fractions having a Rf = 0.20 by TLC (methanol / chloroform, 5/95) are pooled and concentrated to give the title compound, mp 172-175 ° C; MS (ESI +) for C 22 H 23 N 4 O 5 F m / z 433 (M + H) +; [Î ±] 25D = -17 (c 1.04, DMSO).

Step 2: Preparation of (5R) -3- [3-fluoro-4- [4 - [(phenylmethoxy) acetyl] -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of phenylmethyl (-) - 4- [4 - [(5R) -5- (aminocarbonyl) -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylate (Step 1, 415 mg, 0.938 mmol) and 10% palladium on carbon (100 mg, 0.0938 mmol) in methanol (45 mL) is shaken under a 40 psi hydrogen atmosphere in a Parr apparatus for 4 h. The catalyst is then removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure to give 290 mg (100%) of intermediate (5R) -3 - [(3-fluoro -4-piperazinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 135 Ρε1478629 [MS (ESI +) for C 14 H 17 N 4 O 3 F m / z 309 (M + H) +] which is used without further purification. A mixture of this intermediate (240 mg, 0.778 mmol) in methylene chloride (7.8 mL) under nitrogen is treated with triethylamine (163 μl, 1.17 mmol, 1.17 mmol) followed by benzyloxyacetyl chloride (135 μ, 0.856 mmol) , and the resulting homogeneous mixture is stirred at room temperature for 3 h. The reaction mixture is then diluted with water (20 mL) and methylene chloride (20 mL), the layers are separated, and the organic phase is washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on a Flash 40M cartridge of 90 g silica gel (32-63 μl), eluting with methanol / methylene chloride (2.5 / 97.5). Combining and concentrating the fractions with a Rf = 0.50 by TLC (methanol / chloroform, 10/90) affords the title compound.

1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.61 (s, 1H), 7.52 (dd, 1H), 7.36 (m, 4H), 7 (M, 1H), 5.01 (dd, 1H), 4.53 (s, 2H), 4.25 (m, 1H) 3H), 3.97 (dd, 1H), 3.58 (m, 4H), 2.96 (m, 4H); MS (ESI +) for C 23 H 25 FN 4 O 5 m / z 457 (M + H) +.

Step 3: Preparation of (5R) - (-) - 3- [3-fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of (5R) -3- [3-fluoro-4- [4 - [(phenylmethoxy) acetyl] -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinecarboxamide (Step 2, 260 mg (61 mg, 0.0570 mmol) in a mixture of methanol (5 mL) and EtOH (23 mL) is shaken under a 40 psi hydrogen atmosphere in an apparatus of Parr for 22 h. The catalyst is then removed by filtration through a pad of Celite, rinsing with tetrahydrofuran (200 mL), and the filtrate is concentrated under reduced pressure and triturated with methanol / diethyl ether. Filtration then affords the title compound, mp 232-235 ° C (dec.); MS (ESI +) for C 16 H 19 FN 40 m / z 367 (M + H) +; [Î ±] 25D-20 (c 0.98, DMSO). EXAMPLE 15 (5R) - (-) - 3- [4- (thiomorpholin-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide S-D-

Step 1: Preparation of 4- (2,6-Difluoro-phenyl) thiomorpholine 1,1-dioxide

Aluminum chloride (310 g, 2.3 mol) is added to chlorobenzene (2.5 L) to give a turbid green suspension. Vinyl sulfone (230 mL, 2.3 mol) is added via funnel, followed by 2,6-difluoroaniline (250 mL, 2.3 mol). The tan solution is heated to 110 ° C. After the reaction is complete, the heat is removed and the black solution is self-cooled to 70øC. The reaction mixture is then quenched with methylene chloride (4 137 ΡΕ1478629 L) and ice-water (5 L), the aqueous phase is extracted with methylene chloride (3 L, 2 L, 2 L, 2 L ) and the combined organic layers are concentrated, rediluted with branched octane (3 L), and then cooled to 0øC for 30 minutes. The solids are filtered and washed with branched octane (2 x 500 mL) and are then dissolved in methylene chloride (3 L) and loaded onto a plug of silica gel (1.8 kg). The column is eluted with dichloromethane (16 L) until clear. The methylene chloride solution is concentrated, and the solids are dissolved in hot ethyl acetate (3 L), followed by the addition of hexanes (900 mL). The black solution is self-cooled to room temperature overnight, and the resulting clear amber crystal scuffs are filtered and washed with hexanes (4 x 250 mL). The solids are dried under reduced pressure at 50 ° C overnight to give the title compound, 1 H NMR (CDCl 3) δ 7.08 (m, 1H), 6.91 (m, 2H), 3.67 (m, 4H), 3.18 (m, 4H).

Step 2: Preparation of 4- (2,6-Difluoro-4-nitrophenyl) thiomorpholine 1,1-dioxide

To a suspension of 4- (2,6-difluorophenyl) thiomorpholine 1,1-dioxide (Step 1, 300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL, ca. mol, fumarate, 90%) is added over 30 minutes at room temperature. A yellow precipitate forms within minutes and increases over time. The reaction is kept at room temperature for 18 h and is then poured into water. After stirring for 2 h, the yellow suspension is filtered. The precipitate is washed with water (1.5 L x 3) and ethanol (0.5 L x 2) and dried at 50 ° C to give the title compound, 1 H NMR (DMSO- d6) δ 8.05 (m, 2H), 3.69 (m, 4H), 3.26 (m, 4H).

Step 3: Preparation of 4- (1,1-dioxido-4-thiomorpholinyl) -3,5-difluoroaniline To an autoclave is added 4- (2,6-difluoro-4-nitrophenyl) thiomorpholine 1,1-dioxide ( Step 2, 7.0 kg, 24 moles, 1.0 eq). Raney nickel (1.4 kg) is activated and suspended in tetrahydrofuran (4 L), and the slurry is added to the autoclave followed by further tetrahydrofuran (66 L). The mixture is heated at 40 ° C under a 40 psi hydrogen atmosphere until the reaction is complete. The mixture is then filtered, and the filtrate is directly used in the next step. A small portion of the filtrate can be concentrated and recrystallized from isopropanol to give the title compound as pure, (DMSO-d 6) δ 6.17 (m, 2H), 5.35 (s, 2H) 32 (m, 4H), 3. (m, 4H).

Step 4: Preparation of isobutyl 4- (1,1-dioxido-4-thiomorpholinyl) -3,5-difluorophenylcarbamate To a 400 L glass-jacketed reactor containing the solutions of 4- (1,1-dioxido-4- (Step 3, 12.6 kg, 48 mol, 1.0 eq) is added a 47% solution of potassium iodide (14.1 kg, 48 mol, 1.0 eq). The mixture is heated to approximately 45øC, and isobutyl chloroformate (7.2 kg, 53 moles, 1.1 eq) is added while maintaining a reaction temperature between 45øC and 55øC. The reaction is stirred at 45-55 ° C. Once complete, the reaction is quenched by the slow addition of water (45 L) over 15 minutes. The reaction mixture is cooled to 25 ° C and the phases are separated. The tetrahydrofuran solution is exchanged to a suspension in isopropanol (150 L) / water (50 L), and the slurry is slowly cooled to 5øC. The yellow slurry is then filtered and the cake washed with cold isopropanol (2 x 30 L). The yellow solids are dried with nitrogen at 60øC to give the title compound, NMR (CDCl3) δ 7.02 (m, 2H), 6.81 (s, 1H), 3.95 (d, 2H ), 3.60 (m, 4H), 3.17 (m, 4H), 1.97 (m, 1H), 0.94 (d, 6H).

Step 5: Preparation of (5R) - (-) - 3- [4- (thio-morpholin-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide S,

Following the general procedure of EXAMPLE 14, Step 1, and making non-basic variations, but substituting benzyl 4- (4 - {[benzyloxycarbonyl] amino} -2-fluoro-phenyl) -1-piperazinecarboxylate for 4- (1,1 4-thiomorpholinyl) -3,5-difluorophenylcarbamate (Step 4) and purifying the final product by trituration and filtration from (10% methanol / chloroform) / diethyl ether, there is obtained title compound, mp 245-248 ° C (dec.); MS (ESI +) for C 14 H 15 F 2 N 3 O 5 S 376 (M + H) +; 140 ΔΕ1478629 [α] 25d -22 (c 1.00, DMSO). EXAMPLE 16 (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-

oxo-5-oxazolidinecarboxamide - Method C

O

Step 1: Preparation of ethyl (5R) -3- [3-fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinecarboxylate

A solution of 3-fluoro-4-morpholinoaniline (J.

Med. Chem. 1996, 39 (3), 673-679, 0.796 g, 4.0 mmol), ethyl 2 (R) -epoxypropanoate (0.666 g, 6.0 mmol) and lithium triflate (0.97 g, , 2 mmol) in acetonitrile (12 mL) is stirred at 50-60 ° C overnight. Solvent and excess epoxide are removed under reduced pressure, and the crude aminoalcohol is redissolved in dry acetonitrile (40 mL) and 1,1'-carbonyldiimidazole (1.46 g, 9.0 mmol) is added. The mixture is stirred at room temperature overnight, and then the solvent is removed under reduced pressure. The residue is partitioned between ethyl acetate (70 mL) and 3% aqueous citric acid (100 mL), the layers are separated, and the organic phase is washed with 3% aqueous citric acid (3 x 100 mL), water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product mixture is then purified by silica gel chromatography, eluting with ethanol (methylene chloride) (141/86), and the appropriate fractions are pooled and concentrated to give the title compound , MS (ESI +) for C 16 H 19 N 2 O 5 F m / z 339 (M + H) +.

Step 2: Preparation of (5R) - (-) - 3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide

A mixture of ethyl (5R) -3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1, 0.22 g, 0.65 mmol) in ammonia 2M in methanol (5-6 mL) is heated in a closed vial at 60øC for about 1 h. The resulting mixture is cooled to room temperature and concentrated under reduced pressure, and the crude product is recrystallized from methanol to give the title compound, MS (ESI +) for C 14 H 16 N 3 O 4 F m / z 310 (M + H) + . EXAMPLE 17 (5R) - (-) - 3- [3,5-Difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of butyl (5R) -3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylate 142 ΡΕ1478629

A solution of 3,5-difluoro-4- (4-morpholinyl) aniline (See U.S. Patent No. 5,688,792, 2,00 g, 9,34 mmol), butyl 2 (R) -glycidate (2.02 14.0 mmol) and lithium triflate (2.18 g, 14.0 mmol) in acetonitrile (37 mL) is stirred at 60 ° C under N 2 for 48 h. The solvent is removed under reduced pressure, and the residue is taken up in MeOH / CH 2 Cl 2 (5/95, 100 mL), washed with water (2 x 25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is bubbled through a Flash 40M cartridge of 90 g of silica gel with EtOAc / CH 2 Cl 2 (10/90), and the appropriate fractions are pooled and concentrated to give the aminoalcohol intermediate [Rf = 0.10 by TLC , EtOAc / hexanes (25/75)] which is contaminated with residual starting material. This intermediate (2.5 g in two batches) is then dissolved in acetonitrile (70 mL total) and treated with 1,1'-carbonyldiimidazole (total of 1.69 g, 10.4 mmol, 1.5 equiv.), and the reaction mixtures are stirred at room temperature for 6 days and then concentrated under reduced pressure. The product mixtures are each taken up in CH 2 Cl 2 (50 mL), washed with 0.1 M hydrochloric acid (2 x 20 mL) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a Flash 40M Cartilage of 90 g silica gel with EtOAc / CH 2 Cl 2 (5/95). Fractions with a Rf = 0.16 by TLC (EtOAc / hexanes, 25/75) are pooled and concentrated to give the title compound, mp 99-100 ° C; MS (ESI +) for C 18 H 22 N 2 O 5 F 2 m / z 385 (M + H) +. 143 ΡΕ1478629

Step 2: Preparation of (5R) - (-) - 3- [3,5-Difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide O (5R) -3- [3,5 butyl ester (Step 1, 350 mg, 0.910 mmol) is treated with 7N ammonia in methanol (9.1 mL) under N 2, and to afford the title compound as a white solid. The mixture is stirred at room temperature for 30 mins. The reaction mixture is then concentrated under reduced pressure, and the residue is recrystallized from EtOAc / hexanes to give the title compound, mp 181-183 ° C; MS (ESI +) for C 14 H 15 N 3 O 4 F 2 m / z 328 (M + H) +; [Î ±] 25D-23 (c 0.94, DMSO). EXAMPLE 18 (5R) - (-) - 3- [4- (Thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-dioxide

Step 1: Preparation of butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

A solution of 4- (4-thiomorpholinyl) aniline (See

Med. Chem. (1999), 9 (3), 149-161, 2.60 g, 13.4 mmol), butyl 2 (R) -glycidate (2.89 g, 20.1 mmol) and lithium triflate 13 g, 20.1 mmol) in acetonitrile (54 mL) is stirred at 60 ° C under N 2 for 36 h. The solvent is removed under reduced pressure, and the residue is taken up in MeOH / CH 2 Cl 2 (5/95, 100 mL), washed with water (50 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is bubbled through a Flash 40M cartridge of 90 g silica gel with EtOAc / CH 2 Cl 2 (15/85), and the appropriate fractions are pooled and concentrated to give the aminoalcohol intermediate [Rf = 0.19 per TLC , EtOAc / hexanes (25/75)] which is contaminated with the dialkylated by-product. This intermediate (4.25 g) is then dissolved in acetonitrile (125 mL) and treated with 1,1'-carbonyldiimidazole (3.05 g, 18.8 mmol, 1.5 equiv), and the mixture The reaction is stirred at ambient temperature for about 3 days and then concentrated under reduced pressure. The product mixture is taken up in CH 2 Cl 2 (100 mL), washed with 0.1 M hydrochloric acid (3 x 25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on a Carthusian Flash 40M of 90 g of silica gel with EtOAc / CH 2 Cl 2 (15/85). Those fractions having a Rf = 0.57 by TLC (EtOAc / hexanes, 50/50) are pooled and concentrated to give the title compound, mp 95.598øC; MS (ESI +) for C 18 H 24 N 2 O 4 S m / z 365 (M + H) +.

Step 2: Preparation of butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide

A solution of butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1, 600 mg, 1.65 mmol) in water / acetone ( 25 / 75.32 mL) under N 2 is treated with N-methylmorpholine N-oxide (483 mg, 4.12 mmol) 145 ΡΕ1478629 and osmium tetroxide (2.5% by weight in tBuOH, 1.03 mL , 0.0825 mmol), and the mixture is stirred at room temperature for 18 h. The reaction is then treated with 1/2-saturated aqueous sodium bisulfite (20 mL), diluted with water (20 mL) and extracted with CH2 Cl2 (2 x 50 mL). The combined organic phase is washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the product mixture is chromatographed on a flash cartridge of 40 g of silica gel with MeOH / CH2 Cl2 (1 / 99). Combination of the fractions with a Rf = 0.5 by TLC (MeOH / CHCl 3, 5/95) followed by recrystallization from EtOAc / hexanes gives the title compound, mp 100-102øC; MS (ESI +) for C 18 H 24 N 2 O 6 S m / z 397 (M + H) +.

Step 3: Preparation of (5R) - (-) - 3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S, (Step 2, 400 mg, 1.01 mmol) is treated with 7N ammonia in methanol (10.1 mL ) under N 2, and the mixture is stirred at room temperature for 25 mins. The resulting slurry is then diluted with diethyl ether (5 mL) and filtered to give the title compound, mp 226-228 ° C; MS (ESI-) for C 14 H 17 N 3 O 5 S m / z 338 (M-H) -; [α] 25D -22 (c 0.94, DMSO). EXAMPLE 20 (5R) - (-) - 3- [3-fluoro-4- (thio-morpholin-4-yl) -phenyl] -2-oxo-5-oxazolidinecarboxamide S-dioxide 146 ΡΕ1478629

Step 1: Preparation of Butyl (5R) -3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and making non-basic variations, but substituting 3-fluoro-4- (4-thiomorpholinyl) aniline for 4- (4-thiomorpholinyl) aniline (See J. Med. Chem. 1996, 39 (3), 680-685), the title compound is obtained, mp 128-130 ° C; MS (ESI +) for C 18 H 23 N 2 O 4 FS m / z 383 (M + H) +.

Step 2: Preparation of butyl (5R) -3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide

Following the general procedure of EXAMPLE 18, Step 2, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1), the title compound is obtained, mp 169-171 ° C 147 ΡΕ1478629 (dec.); MS (ESI +) for C 18 H 23 N 2 O 6 FS m / z 415 (M + H) +.

Step 3: Preparation of (5R) - (-) - 3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for butyl (5R) -3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide (Step 2), The title compound was obtained, mp 245-247 ° C (dec.); MS (ESI +) for C 14 H 16 N 3 O 5 FS m / z 358 (M + H) +; [Î ±] 25D-22 (c 0.92, DMSO). EXAMPLE 21 (5R) - (-) - 3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide

Step 1: Preparation of butyl (5 R) -3- [3-fluoro-4- (thio-morpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate Sodium 148 ΡΕ1478629

A solution of sodium periodate (265 mg, 1.24 mmol) in water (5 mL) is treated with a slurry of (5R) -3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] - 2-oxo-5-oxazolidinecarboxylate (EXAMPLE 20, Step 1, 450 mg, 1.18 mmol) in methanol (24 mL), and the mixture is stirred at room temperature for 23 h. The resulting mixture is diluted with water (20 mL) and brine (20 mL) and extracted with CH2 Cl2 (2 x 40 mL), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a flash cartridge of 40 g of silica gel, eluting with a gradient of MeOH / CH 2 Cl 2 (1 / 99-2 / 98), and the fractions with a Rf = 0.37 by TLC (MeOH / CHCl 3 , 5/95) are pooled and concentrated and the residue recrystallized from EtOAc / hexanes to give the title compound, mp 128-129 ° C; MS (ESI +) for C 18 H 23 N 2 O 5 FS m / z 399 (M + H) +.

Step 2: Preparation of (5 R) - (-) - 3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for (5R) -3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide (Step 1) and purifying the product by means of trituration and filtration from hot acetonitrile, the title compound is obtained, mp 264-266 ° C (dec.); MS 149 ΡΕ1478629 (ΙΕΡ +) for C 14 H 16 N 3 O 4 FS m / z 342 (M + H) +; [α] 25D -22 (c 0.39, DMSO). EXAMPLE 22 (5R) - (-) - 3- [3,5-Difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide

Step 1: Preparation of 4- (2,6-difluoro-4-nitrophenyl) thiomorpholine

A solution of 3,4,5-trifluoronitrobenzene (5.00 g, 28.24 mmol) in acetonitrile (60 mL) is cooled to 0 ° C and treated with N, N-diisopropylethylamine (7.38 mL, 42.35 mmol) followed by thiomorpholine (2.98 mL, 29.65 mmol). The ice bath is removed and the reaction mixture is stirred at room temperature under nitrogen for about 24 h, during which time more thiomorpholine (0.1 eq) is added. The solvent is removed under reduced pressure, and the residue is diluted with ethyl acetate, washed with 1N hydrochloric acid (until the washes become acidic), saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. reduced pressure to give the title compound, mp 104-105 ° C. 150 ΡΕ1478629

Step 2: Preparation of 3,5-difluoro-4- (4-thiomorpholinyl) aniline

A solution of 4- (2,6-difluoro-4-nitrophenyl) -thiomorpholine (3.00 g, 11.5 mmol) in tetrahydrofuran (60 mL) is added to a Parr bottle containing a mixture of Raney Nickel (1 g) in water (15 mL) under N 2, and the reaction mixture is shaken in a Parr apparatus under an atmosphere of hydrogen at 40 psi for 24 h. The catalyst is removed by filtration through Celite, rinsing with tetrahydrofuran and water, the filtrate is diluted with water (50 mL) and EtOAc (50 mL), and the layers are separated. The organic phase is washed with brine (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil is chromatographed on a Flash 40M cartridge of 90 g silica gel eluting with EtOAc / heptane (15%). / 85). Combination of the fractions with a Rf = 0.19 by TLC (EtOAc / hexanes, 25/75) gives the title compound, mp 85-86 ° C; MS (ESI +) for C 10 H 12 N 2 F 2 S m / z 231 (M + H) +.

Step 3: Preparation of Butyl (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and making non-basic variations, but substituting 3,5-difluoro-4- (4-thiomorpholinyl) aniline (Step 2) for 4- (4-thiomorpholinyl) aniline title compound, mp 102-103 ° C; MS (ESI +) for C 18 H 22 N 2 O 4 F 2 S m / z 401 151 ΡΕ1478629 (Μ + Η) +.

Step 4: Preparation of butyl (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate,

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for Butyl ester (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 3), the title compound is obtained, 1160 C; MS (ESI +) for C 18 H 22 N 2 O 5 F 2 S m / z 417 (M + H) +.

Step 5: Preparation of (5R) - (-) - 3- [3,5-Difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide (Step 4), the title compound is obtained. m.p. 273-276Â ° C (dec.); MS (ESI +) for C 14 H 15 N 3 O 4 F 2 S m / z 360 (M + H) +; [Î ±] 25D-24 (c 0.96, DMSO). EXAMPLE 23 (5R) -3- [3-Fluoro-4- (cis -tetrahydro-1-oxido-2'-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide 152 ΡΕ1478629

Step 1: Preparation of 2-methylpropyl [3-fluoro-4- (tetrahydro-2 H -thio-pyran-4-yl) phenyl] carbamate

A solution of 2-methylpropyl [3-fluoro-4- (tetrahydro-4-hydroxy-2 H -pyrazan-4-yl) phenyl] carbamate (See Org. ) In trifluoroacetic acid (19 mL, 244 mmol) under N2 is treated with triethylsilane (5.85 mL, 36.6 mmol) dropwise, stirred for 1 h , and then added dropwise to saturated aqueous potassium carbonate (250 mL) with vigorous stirring. The mixture is extracted with diethyl ether (200 mL), and the organic phase is washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Trituration and filtration from diethyl ether / hexanes or ethyl acetate / hexanes gives the title compound, ¹H NMR (CDCl3, 400 MHz; δ 7.26 (m, 1H), 7.11 (t, 1H), 6.97 (m, 1H), 6.59 (brs, 1H), 3.95 (d, 2H), 2.85 (m, 3H), 2.68 (m, 2H ), 2.09 (m, 2H), 1.98 (m, 1H), 1.84 (m, 2H), 0.96 (d, 6H).

Step 2: Preparation of 3-fluoro-4- (tetrahydro-2 H -thiopyran-4-yl) benzenamine 153 ΡΕ1478629

A mixture of 2-methylpropyl [3-fluoro-4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] carbamate (Step 1, 2.12 g, 6.81 mmol) in ethylene glycol mL) is treated with aqueous potassium hydroxide (45%, 25.5 g, 204 mmol) with vigorous stirring, and the mixture is warmed to 95 ° C and stirred at this temperature for 18 h. The reaction is then cooled to room temperature and diluted with water (50 mL) and CH 2 Cl 2 (100 mL), the layers are separated, and the organic phase is washed with water (50 mL) and brine (20 mL) ), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is chromatographed on a Flash 40M cartridge of 90 g silica gel with an EtOAc / heptane gradient (15 / 85-25 / 75), and fractions with a Rf = 0.32 by TLC (EtOAc / hexanes , 25/75) are pooled and concentrated to give the title compound, mp 96-98 ° C; MS (ESI +) for C 19 H 14 NFS m / z 212 (M + H) +.

Step 3: Preparation of butyl (5R) -3- [3-fluoro-4- (tetrahydro-2 H -pyrazan-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and making non-basic variations, but substituting 3-fluoro-4- (tetrahydro-2 H -thiopyran-4-yl) benzenamine for 4- (4-thiomorpholinyl) aniline (Step 2), the title compound is obtained, mp 98-100 ° C; MS (ESI +) for C 19 H 24 NO 4 FS m / z 382 (M + H) +. 154 ΡΕ1478629

Step 4: Preparation of (5R) -3- [3-fluoro-4- (cis -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine- carboxylate

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [3-fluoro-4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 3), there is obtained a mixture of cis and trans sulphoxide products in a ratio of approximately 2: 1. Subsequent purification by preparative HPLC (Chiralcel OD column, EtOH eluent) followed by recrystallization from EtOAc / hexanes affords the title compound, mp 142-145 ° C; MS (ESI +) for C 19 H 24 NO 5 FS m / z 398 (M + H) +.

Step 5: Preparation of (5R) -3- [3-fluoro-4- (cis -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarbonitrile carboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for butyl (5R) -3- [3-fluoro-4- (cis-tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 4), and purifying the product by trituration and filtration at 155 ° F and 147 ° F from hot methanol and acetonitrile, the title compound is obtained, mp 279-281 ° C (dec.); MS (IEP +) for

C 15 H 17 N 2 O 4 FS m / z 341 (M + H) +. EXAMPLE 24 (5R) -3- [3-Fluoro-4- (trans -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (5R) -3- [3-fluoro-4- (trans -tetrahydro-1-oxido-2yl-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine carboxylate butyl

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [3-fluoro-4- (tetrahydro-2R-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 23, Step 3), is obtained a mixture of cis and trans sulfoxide products in a ratio of approximately 2: 1. Subsequent purification by preparative HPLC (Chiralcel OD column, EtOH eluent) followed by recrystallization from EtOAc / hexanes affords the title compound, mp 133-136 ° C; MS (ESI +) for C 19 H 24 NO 5 FS m / z 398 (M + H) +. 156 ΡΕ1478629

Step 2: Preparation of (5R) -3- [3-fluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine- carboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for butyl (5R) -3- [3-fluoro-4- (trans -tetrahydro-1-oxido-2 H -pyrazan-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1), the title compound is obtained, mp 201-203 ° C; EXAMPLE 25 (5R) - (-) - 3- [4- (tetrahydro-2H-thiopyran-4-yl) -piperazine-5-carboxylic acid S-dioxide (M + H) + for C 15 H 17 N 2 O 4 FS phenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 2-methyl-propyl 4-bromophenylcarbamate

A solution of 4-bromoaniline (10.0 g, 58.1 mmol) in tetrahydrofuran (230 mL) is treated with sodium bicarbonate (9.77 g, 116.2 mmol) and water (100 mL) followed by isobutyl chloroformate (8.3 mL, 63.9 mmol), and the mixture is stirred at room temperature for 2 h. The mixture is then diluted with water (100 mL) and EtOAc (100 mL), the layers are separated, and the organic phase is washed with water (50 mL) and brine (50 mL), dried over sodium sulfate magnesium chloride and concentrated under reduced pressure. Recrystallization of the resulting solid from EtOAc / hexanes affords the title compound, mp 95-96 ° C; MS (ESI-) for C11 H14 NO2 Br m / z 270 (M-H) -.

Step 2: Preparation of 2-methylpropyl [4- (tetrahydro-4-hydroxy-2H-thiopyran-4-yl) phenyl] carbamate

A solution of 2-methyl-propyl 4-bromophenylcarbamate (Step 1, 10.0 g, 36.7 mmol) in anhydrous tetrahydrofuran (184 mL) at -78 ° C under N 2 is treated with n-butyllithium (1.6M in hexanes, 48.2 mL, 77.1 mmol) dropwise over 20 mins, and the mixture is stirred at -78 ° C for 45 mins. The resulting slurry is then treated with a solution of tetrahydro-2H-thiopyran-4-one (4.48 g, 38.5 mmol) in anhydrous tetrahydrofuran (38 mL) dropwise over min to give an opaque mixture which is allowed to warm slowly to 0 ° C with stirring over about 2.5 h. The mixture is then quenched by the slow addition of saturated aqueous ammonium chloride (75 mL), water (75 mL) is added, and the layers are separated. The organic phase is washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the crude product is recrystallized from EtOAc / hexanes to give 158 ΡΕ1478629 title compound, mp 150-151 ° C; MS (ESI-) for C 16 H 23 NO 3 S m / z 308 (M-H) +.

Step 3: Preparation of 2-methylpropyl [4- (tetrahydro-2 H -pyroman-4-yl) -phenyl] carbamate

Following the general procedure of EXAMPLE 23,

Step 1, and making non-basic variations, but replacing methylpropyl 2- [3-fluoro-4- (tetrahydro-4-hydroxy-2 H -thiopyran-4-yl) phenyl] carbamate with [4- (tetrahydro- dihydro-4-hydroxy-2 H -thiopyran-4-yl) phenyl] carbamate (Step 2) and purifying the product by recrystallization from EtOAc / hexanes, the title compound , mp 126-128 ° C; MS (ESI-) for C 16 H 23 NO 2 S m / z 292 (M-H) -.

Step 4: Preparation of 4- (tetrahydro-2 H -pyrazanan-4-yl) benzenamine

Following the general procedure of EXAMPLE 23,

Step 2, and making non-basic variations, but replacing 2-methylpropyl [3-fluoro-4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] carbamate with [4- (tetrahydro-2H pyridin-4-yl) phenyl] carbamate (Step 3), the title compound is obtained, mp 103-106øC; MS (ESI +) for CnHisNS m / z 194 (M + H) +.

Step 5: Preparation of butyl (5R) -3- [4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate 159 ΡΕ1478629

Following the general procedure of EXAMPLE 18,

Step 1, and making non-basic variations, but substituting 4- (4-thiomorpholinyl) aniline for 4- (tetrahydro-2 H -thiopyran-4-yl) benzenamine (Step 4), the title compound is obtained, mp 94-96 ° C; MS (ESI +) for C 19 H 25 NO 4 S m / z 364 (M + H) +.

Step 6: Preparation of butyl (5 R) -3- [4- (tetrahydro-2 H -pyrazan-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18,

(2R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [4 - (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 5), the title compound is obtained, mp 176-178øC; MS (ESI +) for C 20 H 12 NO 4 S m / z 396 (M + H) +.

Step 7: Preparation of (5R) - (-) - 3- [4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid S, carboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for (5R) -3- [4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-hydroxy-5-oxazolidinecarboxylate (Step 6) , the title compound is obtained, mp 211-212 ° C; MS (ESI-) for CysHisNsOsS m / z 337 (M-H) [Î ±] 25D-19 (c 0.95, DMSO). EXAMPLE 26 (5R) -3- [4- (cis-tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of butyl (5R) -3- [4- (cis-tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 25, Step 5), a mixture of cis sulfoxide products and trans in a ratio of about 2: 1. Subsequent purification by preparative HPLC (Chiralcel OD column, EtOH eluent) followed by recrystallization from EtOAc / hexanes affords the title compound, mp 127-130 ° C; MS (ESI +) for C 19 H 25 NO 5 S m / z 380 (M + H) +. 161 ΡΕ1478629

Step 2: Preparation of (5R) -3- [4- (cis-tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- (5R) -3- [4- (cis-tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1) , the title compound is obtained, mp 269-273 ° C (dec.); MS (ESI-) for C 15 H 18 N 2 O 4 S m / z 321 (M-H) +. EXAMPLE 27 (5R) -3- [4- (trans, s-tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of butyl (5R) -3- [4- (trans-tetrahydro-1-oxy-2-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 25, Step 5), there is obtained a of cis and trans sulfoxide products in a ratio of about 2: 1. Subsequent purification by preparative HPLC (Chiralcel OD column, EtOH eluent) followed by recrystallization from EtOAc / hexanes affords the title compound, mp 115-117 ° C; MS (ESI +) for C 19 H 25 NO 5 S m / z 380 (M + H) +.

Step 2: Preparation of (5R) -3- [4- (trans-tetrahydro-1-oxy-2-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for butyl (5R) -3- [4- (trans -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1), The title compound was obtained, mp 174-175 ° C; MS (ESI-) for C 15 H 18 N 2 O 4 S m / z 321 (M + -).

EXAMPLE 28 (5R) -3- [4- (tetrahydro-2H-thio-pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide S-dioxide -Method B

Step 1: Preparation of 2-methylpropyl [4- (tetrahydro-1,1-dioxido-2 H -pyrazan-4-yl) -3-fluorophenyl] carbamate 163 ΡΕ1478629

Following the general procedure of EXAMPLE 18, Step 2, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for EXAMPLE 23, Step 1), the title compound is obtained, 1 H NMR (CDCl 3) (δ): 7.6 (1H, br s) , 7.38 (bs, 1H), 3.95 (d, 2H), 3.14 (t, 1H), 6.99 (m, 1H) m, 4H), 3.07 (m, 1H), 2.38 (m, 2H), 2.18 (m, 2H), 1.95 (m, 1H), 0.96 (d, 6H).

Step 2: Preparation of (5R) -3- [4- (tetrahydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -5-hydroxymethyl-2-oxazolidinone S,

A solution of 2-methylpropyl [4- (tetrahydro-1,1-dioxido-2 H -pyrazan-4-yl) -3-fluorophenyl] carbamate (Step 1, 2.00 g, 5.82 mmol) in tetrahydrofuran dried at -78 ° C under N2 is treated with n-butyllithium (1.6M in hexanes, 3.82 mL, 6.11 mmol) dropwise and stirred at -78 ° C for 45 mins. Then glycidyl (R) -butyrate (0.86 mL, 6.11 mmol) is added dropwise, and the resulting mixture is stirred at -78 ° C for 30 mins and at ambient temperature for 2.75 days . The reaction mixture is then quenched with saturated aqueous ammonium chloride (15 mL), diluted with water (15 mL) and EtOAc (25 mL), and the layers are separated. The organic phase is diluted with small amounts of methylene chloride, methanol and tetrahydrofuran in an attempt to dissolve a precipitate that has formed and is then washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting solid is then diluted with hot methanol / EtOAc (1: 5, 100 mL), followed by hexanes (150 mL), and filtered to give the title compound, 1 H NMR (DMSO) δ 7.51 (d, 1H), 7.37 (t, 1H), 7.30 (m, 1H), 5.21 (t, 1H) , 3.81 (dd, 1H), 3.65 (m, 1H), 3.55 (m, 1H), 3.37 (m, 2H), 3.20 (m, 1H), 3.10 Step 3: Preparation of (5 R) -3- [4- (tetrahydrofuran-2-yl) dihydro-2H-thiophen-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxylate

A mixture of ruthenium (III) trichloride (29 mg, 0.139 mmol, 4 mol%), sodium periodate (3.21 g, 15.0 mmol), and sodium dihydrogenphosphate monohydrate g, 18.8 mmol) in water / methylene chloride (10: 1, 21 mL) is treated with a suspension of (5 R) -3- [4- (tetrahydro-2 H -thiopyran -4-yl) -3-fluorophenyl] -5-hydroxymethyl-2-oxazolidinone (Step 2, 1.20 g, 3.49 mmol) in acetonitrile (35 mL), and the resulting mixture is stirred at room temperature for 24 hours. H and then adjusted to pH 2 with aqueous hydrochloric acid (1M) and extracted with methylene chloride (3 x 100 mL). The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is bubbled through a Flash 40M Cartilage of 90 g silica gel with a gradient of 165 Å AND 7478629 CH 3 CN / CH 2 Cl 2 (20 / 80-40 / 60) containing 1% formic acid. Fractions containing the carboxylic acid intermediate (920 mg total) are pooled and concentrated, and the white solid is dissolved in methanol (25 mL) and treated with 3 to 4 drops of concentrated sulfuric acid. The resulting mixture is stirred at room temperature for 4 h and is then concentrated under reduced pressure and chromatographed on a flash cartridge of 40 g of silica gel, eluting with a gradient of MeOH / CH 2 Cl 2 (1 99-298 ). Combination of the fractions with a Rf = 0.53 by TLC (MeOH / CH 2 Cl 2, 5/95) affords the title compound as an amorphous solid, ¹H NMR (CDCl 3) δ 7.50 (dd, 1H), 7.25 (t, 1H), 7.15 (m, 1H), 5.09 (dd, 1H), 4.27 (t, 1H), 4.13 (dd, , 88 (s, 3H), 3.15 (m, 4H), 3.11 (m, 1H), 2.40 (m, 2H), 2.19 (m, 2H).

Step 4: Preparation of (5R) -3- [4- (tetrahydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide, S-

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for methyl (5 R) -3- [4- (tetrahydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide (Step 3 ) and purifying the product by trituration and filtration from (5% MeOH / CH2 Cl2) / Et2 O, the title compound is obtained, mp 231-234 ° C (dec.); MS (ESI-) for C 15 H 17 FN 2 O 5 S m / z 355 166 ΡΕ1478629 (Μ-Η). EXAMPLE 29 (5R) - (-) - 3- (2,3-Dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide C: H3

Step 1: Preparation of 6-amino-3-methyl-2 (3H) -benzothiazole

A mixture of 6-nitro-3-methyl-2-benzothiazolinone (J. Heterocyclic Chem. 1992, 29, 1069-1076, 4.85 g, 23.1 mmol) and 10% palladium- , 0.461 mmol) in a mixture of MeOH (45 mL) and tetrahydrofuran (45 mL) is shaken under a 40 psi hydrogen atmosphere in a Parr apparatus for 17 h. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure and triturated with ethyl acetate / hexanes. Filtration then affords the title compound, mp 188-190øC; MS (ESI +) for C 8 H 8 N 2 OS m / z 181 (M + H) +.

Step 2: Preparation of butyl (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate 167 ΡΕ1478629

Following the general procedure of EXAMPLE 18, Step 1, and making non-basic variations, but substituting 6-amino-3-methyl-2 (3H) -benzothiazolone for 4- (4-thiomorpholinyl) aniline (Step 1), there is obtained the title compound, mp 85-87 ° C; MS (ESI +) for C 16 H 18 N 2 O 5 S m / z 351 (M + H) +.

Step 3: Preparation of (5R) - (-) - 3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide Butyl (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (Step 2, 685 mg, 1.95 mmol) is treated with ammonia 7N in MeOH (19 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) and tetrahydrofuran (20 mL) and stirred at room temperature for 1 h. The resulting slurry is concentrated under reduced pressure and then triturated and filtered from acetone to give the title compound, mp 274-276øC (dec.); MS (ESI-) for C 12 H 11 N 3 O 4 S m / z 292 (Μ-H) -; [α] 25D -27 (c 0.98, DMSO). EXAMPLE 30 (5R) - (-) - 3- (2,3-Dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

Step 1:

Preparation of 6-nitro-3-ethyl-2 (3H) -benzothiazolone 168 ΡΕ1478629

A solution of 6-nitro-2-benzothiazolinone (2.5 g, 12.7 mmol) in anhydrous N, N -dimethylformamide (25 mL) under N 2 is treated with 1,8-diazabicyclo [5.4.0] undec-7 (2.48 mL, 16.6 mmol) dropwise followed by iodoethane (22 mL, 15.3 mmol). Following a slight exotherm, the reaction mixture is stirred at room temperature for 21 h, diluted with water (20 mL) and filtered to give the title compound, mp 200-203øC.

Step 2: Preparation of 6-amino-3-ethyl-2 (3H) -benzothiazolone

Following the general procedure of EXAMPLE 29, Step 1, and making non-basic variations, but substituting 6-nitro-3-ethyl-2 (3H) -benzothiazolone for 6-nitro-3-methyl-2 (3H) -benzothiazolone 1), the title compound is obtained, mp 132-133 ° C; MS (ESI +) for C 9 H 10 N 2 OS m / z 195 (M + H) +.

Step 3: Preparation of Butyl (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate

A solution of 6-amino-3-ethyl-2 (3H) -benzothiazolone (Step 2.790 mg, 4.07 mmol), butyl (2R) -glycidate (0.880 g, 6.10 mmol) and lithium triflate (0.952 g, 6.10 mmol) in acetonitrile (16 mL) is stirred at 60 ° C under N 2 for 18 h. The solvent is removed under reduced pressure, and the residue is taken up in MeOH / CH 2 Cl 2 (5/95, 50 mL), washed with water (50 mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. reduced pressure 169 Âμl 147,72929 to give the crude aminoalcohol intermediate [Rf = 0.37 by TLC, EtOAc / hexanes (50/50)] which is transported without further purification. This intermediate is then dissolved in acetonitrile (41 mL) and treated with 1,1'-carbonyldiimidazole (0.989 g, 6.10 mmol), and the reaction mixture is stirred at ambient temperature for approximately 3 days and , then concentrated under reduced pressure. The product mixture is taken up in MeOH / CH 2 Cl 2 (10/90, 50 mL), washed with 0.1 M hydrochloric acid (2 x 30 mL) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated under pressure reduced and chromatographed on a Flash 40M cartridge of 90 g of silica gel with an EtOAc / hexanes gradient (25/75-50 / 50). Fractions with a Rf = 0.35 by TLC (EtOAc / hexanes, 50/50) are pooled and concentrated to give the title compound, mp 99-102 ° C; MS (ESI +) for C 17 H 20 N 2 O 5 S m / z 365 (M + H) +.

Step 4: Preparation of (5R) -3- (2,3-Dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide - (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazole-25 (c 0.92, DMSO).

(Step 3, 500 mg, 1.37 mmol) is treated with 7N ammonia in MeOH (14 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) ) and stirred at room temperature for 30 mins. The resulting slurry is filtered to give the title compound, mp 211-212.5 ° C; MS (ESI +) for C 13 H 13 N 3 O 4 S m / z 308 (M + H) +; [Î ±] 25D 170 Î »E1478629 EXAMPLE 31 (5R) - (-) - 3- (2,3-Dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3-isopropyl-2 (3H) -benzo-thiazolone

A stirred solution of 6-nitro-2-benzothiazolinone (5.0 g, 25.5 mmol) in anhydrous N, N-dimethylformamide (51 mL) under N 2 is treated with 1,8-diazabicyclo [5.4.0] undec- 7-ene (4.96 mL, 33.1 mmol) dropwise. Following a slight exotherm, the reaction mixture is warmed to 50 ° C and treated with 2-iodopropane (12.7 mL, 127 mmol). The resulting mixture is rapidly warmed to 75øC, stirred at this temperature for 40 mins, cooled to room temperature and diluted with ice (100 mL) and water (100 mL). The precipitate is isolated by filtration and recrystallized from ethyl acetate / hexanes to give the title compound, mp 138-142 ° C.

Step 2: Preparation of 6-amino-3-isopropyl-2 (3H) -benzo-zolone 171 ΡΕ1478629

Following the general procedure of EXAMPLE 29, Step 1, and making non-basic variations, but substituting 6-nitro-3-isopropyl-2 (3H) -benzothiazolone for 6-nitro-3-methyl-2 (3H) -benzothiazolone 1), the title compound is obtained, mp 146-148 ° C.

Step 3: Preparation of methyl (5R) -3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate

A vigorously stirred slurry of 6-amino-3-isopropyl-2 (3H) -benzothiazolone (Step 2, 2.90 g, 13.9 mmol) and methyl (2R) -glycidate (1.49 g, 14.6 mmol) in anhydrous acetonitrile (7 mL) under N 2 is heated to 70øC, lithium triflate (2.28 g, 14.6 mmol) is added, and the resulting homogeneous mixture is heated to reflux (heating bath of 95-100Â ° C) and monitored by HPLC. After 1 h, the solvent is removed under reduced pressure, and the residue is taken up in MeOH / CH 2 Cl 2 (5/95, 50 mL), washed with water (50 mL) and brine (25 mL), dried over sodium sulfate. sodium salt and concentrated under reduced pressure to give the crude aminoalcohol intermediate. This intermediate is then dissolved in acetonitrile (70 mL) and treated with 1,1'-carbonyldiimidazole (3.38 g, 20.9 mmol), and the reaction mixture is stirred at ambient temperature overnight. and then concentrated under reduced pressure. The residue is taken up in CH 2 Cl 2 (100 mL), washed with 0.1 M hydrochloric acid (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Trituration and filtration from MeOH then provides the title compound, mp 161-162 ° C; MS (ESI +) for C 15 H 16 N 2 O 5 S m / z 337 (M + H) +.

Step 4: Preparation of (5R) - (-) - 3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for methyl (5R) -3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (Step 3), is obtained the title compound, mp 183-184.5 ° C; MS (ESI +) for C 14 H 15 N 3 O 4 S m / z 322 (M + H) +; [Î ±] 25d-25 (c 0.90, DMSO). EXAMPLE 32 (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-methyl-2-pyridin-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

Butyl (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) is treated with 2N methylamine in MeOH (8.6 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (10 mL) and stirred at room temperature for 1 h. The resulting slurry is filtered to give the title compound, mp 264-267 ° C; MS (ESI +) for C 13 H 13 N 3 O 4 S m / z 308 (M + H) +; [Î ±] 25D -44 (c 0.92, DMSO). EXAMPLE 33 (5R) - (-) - N-Ethyl-3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32 and making non-basic variations, but substituting 2M methylamine in MeOH for 2M ethylamine in MeOH, the title compound is obtained, mp 224.5-226 ° C; MS (ESI-) for C 14 H 15 N 3 O 4 S m / z 302 (M-H) [Î ±] 25 D -46 (c 0.89, DMSO). EXAMPLE 34 (5R) - (-) - N- (2-Hydroxyethyl) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

A solution of butyl (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2 , 300 mg, 0.856 mmol) in acetonitrile (3.4 mL) is treated with ethanolamine (103 μ, 1.71 mmol) and stirred at room temperature for 18 h. The solvent is removed under reduced pressure, and the crude product is triturated and filtered from hot ethyl acetate to give the title compound, mp 217-219 ° C; MS (ESI +) for C 19 H 18 OS 4: m / z 338 (M + H) +; [Î ±] 25D-43 (c 0.99, DMSO). EXAMPLE 35 (5R) -N- (2-Fluoroethyl) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

CHS

A solution of butyl (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 985 , 2.81 mmol) in pyridine (5.5 mL) in a thick-walled screw cap is treated with fluoroethylamine hydrochloride (2.20 g, 22.1 mmol), and the stirred reaction mixture is placed in an oil bath maintained at 90 ° C for 24 h. The mixture is then cooled to room temperature, diluted with CH 2 Cl 2 (50 mL), washed with 0.2 M hydrochloric acid (25 mL portions until the washings are at pH <2) and brine (25 mL ), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M cartridge of 90 g silica gel with MeOH / CH 2 Cl 2 (1 / 99-2.5 / 97.5) . Fractions with a Rf = 0.32 by TLC (MeOH / CHCl 3, 5/95) are pooled and concentrated and the residue is triturated and filtered from MeOH to give the title compound, mp 201-203øC; MS (ESI-) for C 14 H 14 N 3 O 4 FS m / z 338 (M-H) +. EXAMPLE 36 (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide

(5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 30, Step 3, 300 mg, 0.823 mmol ) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at room temperature for 1 h. The resulting slurry is diluted with Et 2 O (10 mL) and filtered to give the title compound, mp 227-290Â ° C; MS (ESI +) for C 14 H 15 N 3 O 4 S m / z 322 (M + H) +; [Î ±] 25D-43 (c 0.93, DMSO). EXAMPLE 37 (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide ΡΕ1478629 176

Methyl (5R) -3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzo thiazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 31, 89 g, 8.59 mmol) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at room temperature for 45 mins and then filtered to give the title compound, mp 172-173.5 ° C; MS (ESI +) for C 15 H 17 N 3 O 4 S m / z 336 (M + H) +; [α] 25d-43 (c 0.98, DMSO). EXAMPLE 38 (5R) - (-) - 3- (2,3-Dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

H o

Step 1: Preparation of 6-nitro-3-methyl-2 (3H) -benzoxazolone

Following the general procedure of EXAMPLE 30, Step 1, and making non-basic variations, but substituting 6-nitro-2 (3H) -benzoxazolone for 6-nitro-2-benzothiazolinone (&lt; J. Heterocyclic Chem. 1992, 29, 1069 -1076) and iodoethane with iodomethane, the title compound is obtained, 177 Ρε1478629 mp 183-185øC.

Step 2: Preparation of 6-amino-3-methyl-2 (3H) -benzoxazolone

Following the general procedure of EXAMPLE 29, Step 1, and making non-basic variations, but substituting 6-nitro-3-methyl-2 (3H) -benzoxazolone for 6-nitro-3-methyl-2 (3H) -benzothiazolone 1) and using a reaction time of 2 to 3 hours, the title compound is obtained, mp 151-153 ° C; MS (ESI +) for C 8 H 8 N 2 O 2 m / z 165 (M + H) +.

Step 3: Preparation of Butyl (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate

A solution of 6-amino-3-methyl-2 (3H) -benzoxazolone (Step 2, 1.00 g, 6.09 mmol), butyl 2 (R) -glycidate (1.32 g, 9.14 mmol ) and lithium triflate (1.43 g, 9.14 mmol) in acetonitrile (24 mL) is stirred at 65 ° C under N 2 for 6 h, then at room temperature over the weekend. The solvent is removed under reduced pressure, and the residue is taken up in MeOH / CH 2 Cl 2 (5/95, 50 mL), washed with water (20 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. to give the crude aminoalcohol intermediate [MS (ESI +) for C 15 H 20 NO 20 m / z 309 (M + H) +]. This intermediate is then dissolved in acetonitrile (61 mL) and treated with 1,1'-carbonyldiimidazole (1.48 g, 9.13 mmol), and the reaction mixture is stirred at room temperature for 18 h at then concentrated under reduced pressure. The product mixture is taken up in CH2 Cl2 (50 mL), washed with acid hydrochloric acid (2 x 30 mL) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on a Flash 40M cartridge of 90 g of silica gel with EtOAc / CH 2 Cl 2 (10/90). Fractions with a Rf = 0.67 by TLC (EtOAc / CH 2 Cl 2, 25/75) are pooled and concentrated to give the title compound, mp 182-184 ° C; MS (ESI +) for C 16 H 18 N 2 O 6 m / z 335 (M + H) +.

Step 4: Preparation of (5R) - (-) - 3- (2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 30

Step 4, and making non-fundamental variations, but substituting butyl (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate for 5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidine carboxylate, the title compound is obtained, mp> 0 ° C; MS (ESI-) for C 12 H 11 N 3 O 5 m / z 276 (M-H) -; [Î ±] 25D-25 (c 0.94, DMSO). EXAMPLE 39 (5R) - (-) - 3- (2,3-Dihydro-3-ethyl-2-oxo-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3-ethyl-2 (3H) -benzoxazolone 179 ΡΕ1478629

Following the general procedure of EXAMPLE 30, Step 1, and making non-basic variations, but substituting 6-nitro-2 (3H) -benzoxazolone for 6-nitro-2-benzothiazolinone (J. Heterocyclic Chem. 1992, 29, 1069 -1076), the title compound is obtained, mp 133-135 ° C.

Step 2: Preparation of 6-amino-3-ethyl-2 (3H) -benzoxazolone

Following the general procedure of EXAMPLE 29,

Step 1, and making non-fundamental variations, but substituting 6-nitro-3-ethyl-2 (3H) -benzoxazolone for 6-nitro-3-methyl-2 (3H) -benzothiazolone (Step 1) and using a reaction time of 2 to 3 hours, the title compound is obtained, mp 72-80 ° C; MS (ESI +) for C 9 H 10 N 2 O 2 m / z 179 (M + H) +.

Step 3: Preparation of Butyl (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 38,

Step 3, and making non-basic variations, but substituting 6-amino-3-ethyl-2 (3H) -benzoxazolone for 6-amino-3-methyl-2 (3H) -benzoxazolone (Step 2), the title compound is obtained. mp 155-157 ° C; MS (ESI +) for C 17 H 20 NO 206 m / z 349 (M + H) +.

Step 4: Preparation of (5R) - (-) - 3- (2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide 180 ΡΕ1478629

Following the general procedure of EXAMPLE 30, Step 4, and making non-basic variations, but substituting (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo -5-oxazolidinecarboxylate for butyl (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidine carboxylate, there is obtained title compound, mp 234-236 ° C; MS (ESI +) for C 13 H 13 N 3 O 5 m / z 292 (M + H) +; [Î ±] 25D-23 (c 0.91, DMSO). EXAMPLE 40 (5R) - (-) - 3- (2,3-Dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 2- (isopropylamino) -5-nitrophenol

A solution of 2-amino-5-nitrophenol (2.00 g, 13.0 mmol) in absolute EtOH (52 mL) and acetone (14.3 mL, 195 mmol, 15 equiv.) Is treated with (408 mg, 6.49 mmol), the pH is adjusted to 4.5-5.0 with glacial AcOH, and the mixture is stirred at room temperature for 4 days, during which time more acetone (2 x 14.3 mL), sodium cyanoborohydride (3 x 408 mg) and glacial AcOH. The reaction mixture is then readjusted to pH 6, concentrated under reduced pressure, diluted with water (50 mL) and CH 2 Cl 2 (75 mL), and the layers are separated 181 Å AND 7478629. The organic phase is washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M cartridge of 90 g silica gel with EtOAc / heptane (20 mL). / 80). Combination of the fractions with a Rf = 0.59 by TLC (EtOAc / hexanes, 50/50) gives the title compound, mp 108-110 ° C; MS (ESI +) for C 9 H 12 N 2 O 3 m / z 197 (M + H) +.

Step A: A homogeneous mixture of 2- (isopropylamino) -5-nitrophenol (Step 1, 1.86 g, 9.48 mmol ) and 1,1'-carbonyldiimidazole (2.31 g, 14.2 mmol) in anhydrous THF under N 2 is heated to 60øC and stirred at this temperature for 18 h. The solvent is then removed under reduced pressure, and the residue is taken up in CH 2 Cl 2 (50 mL), washed with 0.1 M hydrochloric acid (2 x 50 mL) and brine (25 mL), dried over sodium sulfate. sodium salt and concentrated under reduced pressure. Trituration and filtration from MeOH gives the title compound, mp 175-176.5 ° C. Method B: Following the general procedure of EXAMPLE 31, Step 1, and making non-fundamental variations, but substituting 6-nitro-2 (3H) -benzoxazolone for 6-nitro-2-benzothiazolinone (J. Heterocyclic Chem. 1992, 29, 1069-1076), the title compound is obtained. 182 ΡΕ1478629

Step 3: Preparation of 6-amino-3-isopropyl-2 (3H) -benzoxazolone

Following the general procedure of EXAMPLE 29, Step 1, and making non-basic variations, but substituting 6-nitro-3-isopropyl-2 (3H) -benzoxazolone for 6-nitro-3-methyl-2 (3H) -benzothiazolone 2) and using a reaction time of 2 to 3 hours, the title compound, MS (ESI +) for C 10 H 12 N 2 O 2 m / z 193 (M + H) + is obtained.

Step 4: Preparation of butyl (5R) -3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 38, Step 3, and making non-basic variations, but substituting 6-amino-3-isopropyl-2 (3H) -benzoxazolone for 6-amino-3-methyl-2- (3 H) -benzoxazolone Step 3), the title compound is obtained, mp 86-89 ° C; MS (ESI +) for C 18 H 22 N 2 O 6 m / z 363 (M + H) +.

Step 5: Preparation of (5R) - (-) - 3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate (Step 4), butyl (5R) -3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate the title compound is obtained, mp 182.5-184 ° C; MS (ESI +) for C 14 H 15 N 3 O 5 m / z 306 (M + H) +. EXAMPLE 41 (5R) - (-) - N-methyl-3- [4- (tetrahydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5- oxazolidinecarboxamide

Following the general procedure of EXAMPLE 36 and making non-basic variations, but substituting (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (5R) -3- [4- (tetrahydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide (EXAMPLE 28, Step 3), the title compound is obtained, mp 180.5-182 ° C; MS (ESI +) for C 16 H 19 N 2 O 5 FS m / z 371 (M + H) +; [Î ±] 25D-34 (c 0.94, DMSO). EXAMPLE 42 (5R) - (-) - N-Methyl-3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide ΡΕ1478629 184

(5R) -3- [3,5-Difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 17, Step 1) is treated with 2M methylamine in MeOH ( 0.1 M starting material), and the reaction mixture is stirred at room temperature for 30 mins and then concentrated under reduced pressure. The residue is purified by radial chromatography (4000 micron silica gel rotor; eluent of MeOH / CH 2 Cl 2 (3/97)] to give the title compound, mp 179-181 ° C; MS (ESI +) for C 15 H 17 N 3 O 4 F 2 m / z 342 (M + H) +; [α] 25D -40 (c 0.95, DMSO). EXAMPLE 43 (5R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide

Step 1: Preparation of methyl (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate 185 ΡΕ1478629

A vigorously stirred slurry of 3,5-difluoro-4- (4-thiomorpholinyl) aniline (EXAMPLE 22, Step 2, 10.2 mmol) and methyl (2R) -glycidate (1.14 g, 11.2 mmol) in anhydrous acetonitrile (5 mL) under N 2 is heated to 75øC, lithium triflate (1.74 g, 11.2 mmol) is added, and the resulting homogeneous mixture is heated to reflux (95- 100 ° C) and monitored by HPLC. After 2 h, solvent is removed under reduced pressure, and the residue is taken up in MeOH / CH 2 Cl 2 (10/90, 60 mL), washed with water (30 mL) and brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude aminoalcohol intermediate which is then purified by silica gel chromatography [90 g Flash 40M Carat; eluent EtOAc / CH 2 Cl 2 (5 / 95-10 / 90)]. This intermediate is dissolved in acetonitrile (47 mL) and treated with 1,1'-carbonyldiimidazole (1.16 g, 7.12 mmol, 1.5 eq.), And the reaction mixture is stirred at room temperature for one day to the other and then concentrated to 10-15 mL under reduced pressure and stirred for an additional period of time 5 days. The solvent is removed under reduced pressure, and the residue is taken up in CH 2 Cl 2 (100 mL), washed with 0.1 M hydrochloric acid (2 x 25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. reduced pressure. The crude product is then chromatographed on a Flash 40M cartridge of 90 g silica gel, eluting with EtOAc / CH 2 Cl 2 (5/95), and the fractions with a Rf = 0.53 by TLC (EtOAc / hexanes, 50/50) are pooled and concentrated to provide the title compound, mp 99-101 ° C; MS (ESI +) for C 15 H 16 N 2 O 4 F 2 S m / z 359 (M + H) +. 186 ΡΕ1478629

Step 2: Preparation of methyl (5 R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate S-oxide

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting (5R) -3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1) and purifying the crude product mixture by means of recrystallization from EtOAc / hexanes, the title compound is obtained, mp 123.5-125 ° C; MS (ESI +) for C 15 H 16 N 2 O 5 F 2 S m / z 375 (M + H) +.

Step 3: Preparation of (5R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidine- carboxamide

Following the general procedure of EXAMPLE 36 and making non-basic variations, but substituting (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 2), the compound , mp 237-241 ° C; MS (ESI +) for C 15 H 17 N 3 O 4 F 2 S m / z 374 (M + H) +; [Î ±] 25D-38 (c 0.94, DMSO). EXAMPLE 44 (5R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxy - ΡΕ1478629 187 mida

Step 1: Preparation of methyl (5 R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide

Following the general procedure of EXAMPLE 18, Step 2, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 43, Step 1) and purifying the crude product mixture by means of of recrystallization from EtOAc / hexanes, the title compound is obtained, mp 158.5-161 ° C; MS (ESI +) for C 15 H 16 N 2 O 6 F 2 S m / z 391 (M + H) +.

Step 2: Preparation of (5R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxamide

Following the general procedure of EXAMPLE 36 and making non-basic variations, but substituting (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxylate (5R) -3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidine-4-carboxylate S-dioxide (Step 1 ), the title compound is obtained, mp 243-246 ° C; MS (ESI-) for C 15 H 17 N 3 O 5 F 2 S m / z 388 (M-H) +; [Î ±] 25d-37 (c 1.01, DMSO). EXAMPLE 45 (5R) -3- [3,5-Difluoro-4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 3,5-Difluoroaniline (3.53 g, 26.8 mmol) in toluene / THF (1: 1, 60 mL) are added acetonylacetone (3.24 mL, 26.8 mmol) and p-toluenesulfonic acid monohydrate (0.168 g). The reaction mixture is heated at reflux for 3 h, concentrated under reduced pressure, diluted with CH 2 Cl 2 (60 mL), washed with water (3 x 10 mL) and brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by chromatography on a Flash 40M Cartilage of 90 g of silica gel eluting with EtOAc / Hexanes (5 / 95-10 / 90) affords the title compound, mp 55-56 ° C. 189 ΡΕ1478629

Step 2: Preparation of 4- [4- (2,5-dimethyl-1 H -pyrrol-1-yl) -2,6-difluorophenyl] tetrahydro-2 H -thiopyran-4-ol To the solution of 1- - (3,5-difluorophenyl) -2,5-dimethyl-1H-pyrrole (Step 1, 16.7 g, 80.6 mmol) in anhydrous THF (161 mL) at -78 ° C under N2 is added n- BuLi (1.6 M in hexanes, 51.8 mL, 82.9 mmol) dropwise. After stirring at -78 ° C for 1 h, the reaction mixture is treated with tetrahydrothiopyran-4-one (5.35 g, 46.1 mmol) in anhydrous THF (46 mL) dropwise, and followed by stirring at -78 ° C for 2 h and 0 ° C for 3 h. The reaction is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL), diluted with H 2 O (50 mL) and Et 2 O (50 mL) and the layers are separated. The organic phase is washed with H2O (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue is purified by silica gel chromatography (650 mL, eluent 10-20% EtOAc / Hexanes) to give the title compound, mp 125-126 ° C; MS (ESI +) for C 17 H 19 F 2 NOS m / z 324 (M + H) +.

Step 3: Preparation of 1- [4- (3,6-dihydro-2H-thiopyran-4-yl) -3,5-difluorophenyl] -2,5-dimethyl-1H-pyrrole

A stirred solution of 4- [4- (2,5-dimethyl-1H-pyrrol-1-yl) -2,6-difluorophenyl] tetrahydro-2H-thiopyran-4-ol (Step 2, 1.617 g, , 0.00 mmol) and p-toluenesulfonic acid monohydrate (0.107 g) in benzene (20 mL) is heated at reflux using a Dean-Stark apparatus for 190 Ρ Ρ 7 7872929 5 h, during which time additional monohydrate of p-toluenesulfonic acid (0.342 g). The solvent is then removed under reduced pressure, and the residue is taken up in CH 2 Cl 2 (60 mL), washed with saturated aqueous NaHCO 3 (2 x 20 mL) and water (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on a Flash 40M Cartilage of 90 g silica gel, eluting with 2-5% EtOAc / Hexanes affords the title compound, mp 118-119 ° C; MS (ESI +) for C 17 H 17 F 2 NS m / z 306 (M + H) +.

Step 4: Preparation of 4- (3,6-dihydro-2,7-thiopyran-4-yl) -3,5-difluorobenzenamine To a stirred solution of 1- [4- (3,6-dihydro-2- 4-yl) -3,5-difluorophenyl] -2,5-dimethyl-1 H -pyrrole (0.288 g, 2.71 mmol) in 95% ethanol / THF (10: mL) is added hydroxylamine hydrochloride (3.77 g, 54.2 mmol) and triethylamine (3.8 mL, 27.1 mmol). The reaction mixture is heated to reflux for 2 days and then concentrated under reduced pressure, diluted with CH 2 Cl 2 (60 mL), washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under pressure reduced. Purification by chromatography on a Flash 40M Cartilage of 90 g silica gel, eluting with 10-20% EtOAc / Hexanes, affords the title compound, MS (ESI +) for C 19 H 21 F 2 NS m / z 228 (M + + H) +; 1 H NMR (CDCl 3, 400 MHz) δ 6.22 (m, 2H), 5.91 (m, 1H), 3.83 (m, 2H), 3.33 (m, 2H), 2.86 , 2H), 2.53 (m, 2H). 191 ΡΕ1478629

Step 5: Preparation of isobutyl [4- (3,6-dihydro-2A-thiopyran-4-yl) -3,5-difluorophenyl] carbamate To a stirred, biphasic mixture of 4- (3,6- dihydro-2H-thiopyran-4-yl) -3,5-difluorobenzenamine (Step 4.3, 90 g, 17.2 mmol) in THF / water (2: 1, 103 mL) 88 g, 34.3 mmol) followed by isobutyl carbamate (2.45 mL, 18.9 mmol) dropwise. The reaction mixture is stirred at room temperature for 7 h and is then concentrated under reduced pressure, diluted with EtOAc (100 mL) and H2 O (50 mL), and the layers are separated. The organic phase is washed with H2O (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by chromatography on a Flash 40M Cartilage of 90 g of silica gel, eluting with 5-10% EtOAc / Hexanes affords the title compound, mp 136-1370 ° C; MS (ESI-) for C 16 H 19 F 2 NO 2 S m / z 326 (M-H) -.

Step 6: Preparation of isobutyl [4- (tetrahydro-2H-thiopyran-4-yl) -3,5-difluorophenyl] carbamate Method A: To a stirred solution of [4- (3,6-dihydro-2H 4-yl) -3,5-difluorophenyl] carbamate (Step 5, 5.62 g, 17.2 mmol) in TFA (26.5 mL, 343 mmol) is added triethylsilane (8.23 mL , 51.5 mmol), and the mixture is stirred at 70 ° C for 2.2 days, during which further triethylsilane (2 x 2.74 mL) is added, and at 40 ° C for 192 Ρ Ρ 7 7872929 2.6 days . The reaction is then cooled to room temperature, added slowly to saturated aqueous sodium bicarbonate (300 mL), and extracted with Et 2 O (200 mL). The organic layer is washed with H2 O (2 x 50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue is recrystallized from EtOAc / hexanes to give the title compound, mp 147-149 ° C; MS (ESI-) for C 16 H 21 F 2 NO 2 S m / z 328 (M-H) -. Method B: Step A: Preparation of isobutyl 3,5-difluorophenylcarbamate

Following the general procedure of Step 5, and making non-basic variations but substituting 3,5-difluoroaniline for 4- (3,6-dihydro-2 H -thiopyran-4-yl) -3,5-difluoroaniline, is obtained the title compound, mp 71-74 ° C; MS (ESI-) for C 21 H 28 N 3 O 4 F 2 m / z 228 (M-H) -.

Step B: Preparation of isobutyl [4- (tetrahydro-4-hydroxy-2H-thiopyran-4-yl) -3,5-difluorophenyl] carbamate

A stirred solution of isobutyl 3,5-difluorophenylcarbamate (Step A, 10.0 g, 43.6 mmol) and Ν, Ν, Ν ', Ν'-tetramethylethylenediamine (13.7 mL, 87.3 mmol) in THF (87 mL) at -78 ° C under N 2 is treated with n-butyllithium (1.6M in hexanes, 35.8 mL, 89.4 mmol) dropwise over 35 mins. The mixture is stirred at -78 ° C for 20 mins and is then treated with a solution of tetrahydro-2H-thiopyran-4-one (5.32 g, 45.8 mmol) in dichloromethane. THF (15 mL) was added dropwise over 10 mins. After 45 mins at -78 ° C, the cooling bath is removed and the mixture is allowed to warm to room temperature and is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL). Water (50 mL) and EtOAc (100 mL) are added, the layers are separated, and the organic phase is washed with water (100 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure . The crude product is triturated and filtered from EtOAc (ca. 25 mL) to remove an insoluble impurity, and the filtrate is chromatographed on two flash cartridges of 90 g silica gel, eluting with EtOAc / heptane (20 / 80). Combination of the fractions with a Rf = 0.26 by TLC (EtOAc / hexanes, 25/75) gives the title compound, mp 103-104 ° C.

Step C: Preparation of isobutyl [4- (tetrahydro-2H-thio-pyran-4-yl) -3,5-difluorophenyl] carbamate

Following the general procedure of Step 6, Method A, and making non-basic variations, but substituting [4- (3,6-dihydro-2 H -thiopyran-4-yl) -3,5-difluorophenyl] carbamate isobutyl isobutyl [4- (tetrahydro-4-hydroxy-2 H -thiopyran-4-yl) -3,5-difluorophenyl] carbamate (Step B), the title compound is obtained.

Step 7: Preparation of 3,5-difluoro-4- (tetrahydro-2 H -thiopyran-4-yl) benzeneamine 194 ΡΕ1478629

Following the general procedure of EXAMPLE 23, step 2, and making non-basic variations, but substituting 2-methylpropyl [3-fluoro-4- (tetrahydro-2H-thiopyran-4-yl) phenyl] - (tetrahydro-2H-thiopyran-4-yl) -3,5-difluorophenyl] carbamate (Step 6), the title compound is obtained, mp 118-119 ° C; MS (ESI-) for C 11 H 13 NF 2 S m / z 228 (M-H).

Step 8: Preparation of Butyl (5R) -3- [3,5-difluoro-4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 17,

Step 1, and making non-basic variations, but replacing 3,5-difluoro-4- (4-morpholinyl) aniline with 3,5-difluoro-4- (tetrahydro-2 H -thiopyran-4-yl) benzenamine (Step 7), the title compound is obtained, mp 86-89 ° C; MS (ESI +) for C 19 H 23 NO 4 F 2 S m / z 400 (M + H) +.

Step 9: Preparation of (5R) -3- [3,5-Difluoro-4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazol- butyl dinocarboxylate

Following the general procedure of EXAMPLE 18,

(5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate butyrate for (5R) -3- [3 , 5-difluoro-4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine-1 H -indole carboxylate (Step 8), the title compound is obtained, mp 218 DEG- -220 ° C; MS (ESI +) for C 19 H 23 NO 6 F 2 S m / z 432 (M + H) +.

Step 10: Preparation of (5R) -3- [3,5-difluoro-4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5- oxazolidinocarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for butyl (5R) -3- [3,5-difluoro-4- (tetrahydro-2 H -pyrazan-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide (Step 9), the title compound is obtained, mp 243-245 ° C; MS (ESI-) for C 15 H 16 N 2 O 5 F 2 S m / z 373 (M-H) +. EXAMPLE 46 (5R) - (-) - 3- [3,5-Difluoro-4- (cis -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxine midair

Step 1: Preparation of (5R) -3- [3,5-Difluoro-4- (cis -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine- butyl carboxylate 196 ΡΕ1478629

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [3,5-Difluoro-4- (tetrahydro-2A-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine carboxylate (EXAMPLE 45, Step 8), a mixture of cis and trans sulfoxide products is obtained in a ratio of about 1: 1. Subsequent purification by preparative HPLC (Chiralcel OD column, EtOH eluent) affords the title compound, MS (ESI +) for C 10 H 23 NO 5 F 2 S m / z 416 (M + H) +; NMR (DMSO-d 6, 400 MHz) δ 7.33 (m, 2H), 5.34 (m, 1H), 4.35 (m, 1H), 4.16 (m, 3H), 3.18 (m, m), 2.92 (m, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 1.61 (m, 4H), 1.35 (sext. 0.89 (t, 3H).

Step 2: Preparation of (5R) - (-) - 3- [3,5-difluoro-4- (cis -tetrahydro-1-oxido-2A-thiopyran-4-yl) phenyl] -2- 5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for (5R) -3- [3,5-difluoro-4- (cis -tetrahydro-1-oxido-2A-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate butyl ester (Step 1), the title compound is obtained, mp 283-285 ° C (dec.); MS (ESI +) for C 15 H 16 N 2 O 4 F 2 S m / z 359 (M + H) +; [Î ±] 25D-20 (c 0.94, DMSO). EXAMPLE 47 (5R) - (-) - 3- [3,5-Difluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2- oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (5R) -3- [3,5-Difluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2- 5-oxazo-lidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and making non-basic variations, but substituting butyl (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- [3,5-Difluoro-4- (tetrahydro-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 45, Step 8 ), a mixture of cis and trans sulfoxide products is obtained in a ratio of approximately 1: 1. Subsequent purification by preparative HPLC (Chiralcel OD column, EtOH eluent) affords the title compound, MS (ESI +) for C 19 H 23 NO 5 F 2 S m / z 416 (M + H) +; Δ NMR (DMSO-d6, 400 MHz) δ 7.31 (m, 2H), 5.34 (m, -133 (m, 1H), 4.13 (m, 3H), 3.36 (m 2H), 3.19 (m, 1H), 2.82 (m, 2H), 2.01 (m, 4H), 1.60 (m 2H), 1.33 (sext, 2H), 0.89 (t, 3H) 198 ΡΕ1478629

Step 2: Preparation of (5R) - (-) - 3- [3,5-difluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2- oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 17,

(2R) -3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylate for (5R) -3- (3,5-Difluoro-4-trans -tetrahydro-1-oxido-2 H -pyrazan-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 1) and purifying the The title compound, MS (ESI +) for C 15 H 16 N 2 O 4 F 2 S m / z 359 (M + H) + is obtained, by chromatography on silica gel (2-5% MeOH eluent / CH 2 Cl 2); 1 H NMR (DMSO-d 6, 400MHz) δ 7.87 (bs, 1H), 7.63 (bs, 1H), 7.33 (m, 2H), 5.04 (M, 2H), 2.05 (m, 2H), 3.00 (m, 2H) 4H); [Î ±] 25d-21 (c 0.96, DMSO). EXAMPLE 48 (5R) -N-Methyl-3- (3,5-difluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine -carboxamide

Following the general procedure of EXAMPLE 42 and making non-fundamental variations, but substituting (5R) - 199 ΡΕ1478629

Butyl 3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidine carboxylate for (5R) -3- [3,5-difluoro-4- (trans-tetra (EXAMPLE 47, Step 1) and purifying the product by chromatography on silica gel (eluent 1.5-3% MeOH / CH 2 Cl 2), the title compound is obtained, MS (ESI +) for C 16 H 18 N 2 O 4 F 2 S m / z 373 (M + H); 1 H NMR (DMSO-d 6, 400 MHz) δ 8.40 (m, 1H), 7.32 (m, 2H), 5.07 (dd, 1H), 4.24 (t, 1H), 4.00 (m, 2H), 2.65 (d, 3H), 2.05 (m, 4H), 3.65 (m, . EXAMPLE 49 (5R) -3 - [(2R) -2,3-Dihydro-1-formyl-2-methyl-1H-indol-5-yl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (2R) -2,3-dihydro-2-methyl-1H-indol-5-amine

A mixture of benzyl (2R) -5 - {[(benzyloxy) carbonylamino} -2-methyl-2,3-dihydro-1H-indole-1-carboxylate (PCT / US00 / 08224; WO00 / 73301, , And 10% palladium on carbon (108 mg) in THF / MeOH (1: 1, 60 mL) is shaken in a Parr apparatus under a 36 psi hydrogen atmosphere of day to the next. The catalyst is removed by filtration through a pad of 200 ΡΕ1478629

Celite, and the filtrate is concentrated under reduced pressure. Purification by chromatography on a Flash 40M Cartilage of 90 g silica gel (1-2% MeOH / CH 2 Cl 2) affords the title compound, MS (ESI +) for C 9 H 12 N 2 m / z 149 (M + H) + .

Step 2: Preparation of (2R) -5- (2,5-dimethyl-1 H -pyrrol-1-yl) -2,3-dihydro-2-methyl-indole To a stirred solution of (2R) (Step 1, 0.896 g, 6.05 mmol) in THF (180 mL) is added acetonylacetone (0.732 mL, 6.05 mmol) and p-toluenesulfonic acid (0.008 g). The reaction mixture is stirred at 68øC for 6 h and then concentrated under reduced pressure, and the residue is purified by chromatography on a Flash 40M cartridge of 90 g silica gel (eluent of 10% EtOAc) / Hexanes) to give the title compound, MS (ESI +) for C 15 H 18 N 2 m / z 227 (M + H) +.

Step 3: Preparation of phenyl methyl (2R) -5- (2,5-dimethyl-1 H -pyrrol-1-yl) -2,3-dihydro-2-methyl-1 H -indole-1-carboxylate To a stirred solution of (2R) -5- (2,5-dimethyl-1 H -pyrrol-1-yl) -2,3-dihydro-2-methyl-indole (Step 2, 0.100 gt; 0.442 mmol) in THF / H2 0 (8: 1, 4.5 mL) is added sodium bicarbonate (0.072 g, 0.884 mmol) followed by benzyl chloroformate (80 μe, 0.53 mmol) at 0 ° C. The reaction mixture is stirred at 0øC for 30 mins and at room temperature for 2 h and is then concentrated under reduced pressure. The residue is taken up in CH 2 Cl 2 (40 mL), washed with H 2 O (2 x 10 mL) and brine (2 x 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S Cartography of 40 g silica gel (1% EtOAc / Hexanes) to give the title compound, MS (ESI +) for C 23 H 24 N 2 O 2 m / z 361 (M + + H) +.

Step 4: Preparation of phenylmethyl (2R) -5-amino-2,3-dihydro-2-methyl-1 H -indole-1-carboxylate To a stirred solution of (2R) -5- (2,5- dimethyl-1 H -pyrrol-1-yl) -2,3-dihydro-2-methyl-1 H -indole-1-carboxylate (Step 3, 2.11 g, 5.84 mmol) in water / ethanol (1: 9, 60 mL) are added triethylamine (6.5 mL, 46.7 mmol) and hydroxylamine hydrochloride (6.49 g, 93.4 mmol). The reaction mixture is stirred at 90 ° C for 20 h and is then concentrated under reduced pressure. The residue is taken up in CH 2 Cl 2 (60 mL) and washed with H 2 O (2 x 20 mL) and brine (2 x 20 mL), and the combined aqueous layer is extracted with CH 2 Cl 2 (2 x 20 mL). The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by chromatography on a Flash 40M cartridge of 90 g silica gel (eluent of 30-50% EtOAc / Hexanes) to give the title compound, MS (ESI +) for 202 Ρε1478629 C17H18N2O2 m / z 283 (M + H) +.

Step 5: Preparation of (2R) -2,3-Dihydro-5 - [(5R) -5- (methoxycarbonyl) -2-oxo-3-oxazolidinyl] -2-methyl-1H-indole-1 -phenylmethylcarboxylate

Following the general procedure of EXAMPLE 38, Step 3, and making non-basic variations, but substituting (2R) -5-amino-2,3-dihydroxy-6-amino-3-methyl-2 (3H) -benzoxazolone for (2R) dihydro-2-methyl-1H-indole-1-carboxylate (Step 4) and butyl 2 (R) -glycidate for methyl 2 (R) -glycidate, the title compound is obtained, MS (ESI +) for C 22 H 22 N 2 O 6 m / z 433 (M + Na) +.

Step 6: Preparation of methyl (5R) -3 - [(2R) -2,3-dihydro-1-formyl-2-methyl-indol-5-yl] -2-oxo-5-oxazolidinecarboxylate

A mixture of (2R) -2,3-dihydro-5 - [(5R) -5- (methoxycarbonyl) -2-oxo-3-oxazolidinyl] -2-methyl-1H-indole-1-carboxylate of phenylmethyl (Step 5, 0.211 g, 0.51 mmol) and 10% palladium-on-carbon (0.006 g) in methanol / THF (1: 1, 10 mL) is shaken in a Parr apparatus under an atmosphere of 36 psi of hydrogen for 4 h. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure to give (5R) -3- [2 (R) -2,3-dihydro-2 methyl-1 H -indol-5-yl] -2-oxo-5-oxazolidinecarboxylate which is then dissolved in THF (6 mL) and treated with triethylamine (142 μL, 1.02 mmol) and 1 H- benzotriazole-1-carboxaldehyde (0.092 g, 0.56 mmol). The reaction mixture is stirred at room temperature under N 2 for approximately 18 h, during which additional 1 H -benzotriazole-1-carboxaldehyde (0.046 g, 0.28 mmol) is added, and is then concentrated under reduced pressure. The residue is taken up in CH 2 Cl 2 (40 mL) and washed with H 2 O (2 x 20 mL) and brine (2 x 20 mL). The combined aqueous layer is extracted with CH 2 Cl 2 (2 x 20 mL), and the combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a Flash 40M cartridge of 90 g silica gel (eluent of 50-100% EtOAc / Hexanes) to give the title compound, MS (ESI +) for C 15 H 16 N 2 O 5 m / z 305 (M + H) +.

Step 7: Preparation of (5R) -3 - [(2R) -2,3-dihydro-1-formyl-2-methyl-5-1,2] oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and making non-basic variations, but substituting (5R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxylate for methyl (5R) -3 - [(2R) -2,3-dihydro-1-formyl-2-methyl-1 H -indol-5-yl] -2-oxo-5-oxazolidinecarboxylate ( Step 6), the title compound is obtained, mp 228-230 ° C; MS (ESI +) for C 14 H 15 N 3 O 4 m / e 290 (M + H) +. EXAMPLE 50 (5R) -3 - [(2R) -2,3-Dihydro-1- (hydroxyacetyl) -2-methyl-1H-indol-5-yl] -2-oxo-5-oxazolidinecarboxamide 204 ΡΕ1478629 Ηΰ

Ϊ4Η2

Step 1: Preparation of (5R) -3 - [(2R) -2,3-dihydro-1 - [(phenylmethoxy) acetyl] -2-methyl-1H-indol-5-yl] -2- oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 49, Step 6, and making non-basic variations, but substituting benzyloxyacetyl chloride for 1 H -benzotriazole-1-carboxaldehyde and purifying the product by silica gel chromatography (MeOH eluent 1-2 The title compound, MS (ESI +) for C 23 H 24 N 2 O 6 / m 425 (M + H) +,

Step 2: Preparation of (5R) -3 - [(2R) -2,3-dihydro-1- (hydroxylacetyl) -2-methyl-1H-indol-5-yl] -2-oxo-5- -oxazolidinecarboxylate

A mixture of (5R) -3 - [(2R) -2,3-dihydro-1 - [(phenylmethoxy) acetyl] -2-methyl-1 H -indol-5-yl] -2- 5-oxazolidinecarboxylate (Step 1, 0.301 g, 0.71 mmol) and Pearlman's catalyst (0.032 g) in methanol (30 mL) is shaken in a Parr apparatus under an atmosphere of 36 psi of hydrogen for about 24 hours. h, during which further Pearlman's catalyst (0.044 g) is added. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S silica gel cartridge (2% MeOH / CH 2 Cl 2 eluent) to give the title compound, MS (ESI +) for C 16 H 18 NO 206 m / z 335 ( M + H) +.

Step 3: Preparation of (5R) -3 - [(2R) -2,3-dihydro-1- (hydroxylacetyl) -2-methyl-1H-indol-5-yl] -2-oxo-5- oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18,

(3R) -3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxylate, S-dioxide was reacted with (5R) - Methyl 3 - [(2R) -2,3-dihydro-1- (hydroxyacetyl) -2-methyl-1H-indol-5-yl] -2-oxo-5-oxazolidinecarboxylate (Step 2), is obtained the title compound, mp 198-200 ° C; MS (ESI +) for C 15 H 17 N 3 O 5 m / z 320 (M + H) +. EXAMPLE 51 (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-methyl-2-pyridin-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

T the

Following the general procedure of EXAMPLE 32, and making non-basic variations, but substituting (5R) -206 ΡΕ1478629 3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2- 5-oxazolidinecarboxylate for butyl (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 38, 3), the title compound is obtained, mp 304-6 ° C; MS (ESI-) for C 13 H 13 N 3 O 5 m / z 290 (M +) [α] 25d-34 (c 1.03, DMSO) 3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32, and making non-basic variations, but substituting (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5- oxazolidinecarboxylate for butyl (5R) -3- (2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 39, Step 3), is The title compound was obtained, mp 263-5øC; MS (ESI-) for C 14 H 15 N 3 O 5 m / z 304 (ΜΗ) -; [α] 25d-39 (c 0.94, DMSO). EXAMPLE 53 (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide 207 ΡΕ1478629

Following the general procedure of EXAMPLE 32, and making non-basic variations, but substituting (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5- oxazolidinecarboxylate for butyl (5R) -3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 40, Step 4) , the title compound is obtained, mp 216-8 ° C; MS (ESI-) for C 15 H 17 N 3 O 5 m / z 318 (Μ-α, [α] 15 D- 6H-pyrrolo [3,4-b] pyridin-6-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (5R) -3- [4- (5,7-dihydro-6,7-pyrrolo [3,4-b] pyridin-6-yl) -3-fluorophenyl] -2- 5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 31, Step 3, and making non-basic variations, but substituting 5,7-dihydro-6- (2-fluoro-3-isopropyl-2 (3H) -benzothiazolone for 6-amino- 4-aminophenyl) -6 H -pyrrolo [3,4-b] pyridine hydrochloride 208 ΡΕ1478629 (WO 01/42242; PCT / US00 / 21093) and purifying the product by silica gel chromatography (20-30 EtOAc eluent % / hexanes), the title compound is obtained, mp 239-240 ° C (dec.); MS (ESI +) for C 18 H 16 N 3 O 4 F m / z 358 (M + H) +.

Step 2: Preparation of (5R) -3- [4- (5,7-dihydro-6 H -pyrrolo [3,4-b] pyridin-6-yl) -3-fluorophenyl] -2- (5R) -3- [4- (5,7-dihydro-6H-pyrrolo [3,4-b] pyrimidin-6-yl) -3-fluorophenyl] -2-oxazolidinecarboxamide oxo-5-oxazolidinecarboxylate (Step 1) is suspended in methanol-saturated ammonia (25 mL), stirred at room temperature for 4 hours and filtered to give the title compound, mp 257 ° C (dec.); MS (ESI +) for C 17 H 15 N 4 O 3 F m / z 343 (M + H) +. EXAMPLE 55 (5R) -N-Methoxy-3- [4- (5,7-dihydro-6 H -pyrrolo [3,4- b] pyridin-6-yl) -3-fluorophenyl] -2-oxo -5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32, and making non-basic variations, but substituting (5R) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5- (5R) -3- [4- (5,7-dihydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -3-fluorophenyl] -2-oxo- 5-oxazolidinecarboxylate (EXAMPLE 54, Step 1), the title compound is obtained, mp 275 ° C (dec.); MS (ESI +) for C 18 H 17 N 4 O 3 F m / z 357 (M + H) +. EXAMPLE 56 (5R) -3- [4- (cis-1-Imino-1-oxido-1,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3-fluorophenyl ] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 3-fluoro-4- (cis -tetrahydro-1-oxy-2-2H-thiopyran-4-yl) aniline

A suspension of 2.07 g of 2-methylpropyl [3-fluoro-4- (cis-tetrahydro-1-oxido-2 H -pyrazan-4-yl) phenyl] carbamate (U.S. Patent No. 6,239,283 ) in 25 ml of ethylene glycol is treated with 5 ml of 45% aqueous KOH, placed under N2 and heated with stirring to 90 ° C for 10 h. The resulting dark brown solution is cooled to room temperature, diluted with water and extracted with 5% MeOH / CH 2 Cl 2. The organic extracts are combined, dried (NaS04), filtered and concentrated to give the crude product which is chromatographed on silica gel eluting first with 5% MeOH / EtOAc (to remove a non-polar impurity) followed by elution was treated with 3% MeOH / CHCl 3 (+ 0.1% NH 4 OH) to give the title compound, 210 Å AND 7478629 TLC (UV) Rf = 0.40 in 5% MeOH / CHCl 3 (+ 0.5% NH4OH); MS (+ ESI) for C 19 H 14 FNOS m / z 228 (M + H) +.

Step 2: Preparation of (5R) -3- [3-fluoro-4- (cis -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarbonitrile carboxylate

A suspension of 389 mg (1.71 mmole) of 3-fluoro-4- (cis -tetrahydro-1-oxido-2H-thiopyran-4-yl) aniline (Step 1) in 2 ml CH3 CN is treated with 372 mg (1.74 mmol) LiOTf and 150 μE (1.72 mmol) of methyl (R) -glycidate. This mixture is placed under N2 and heated to 80 ° C with vigorous stirring. After 17 h the reaction is cooled to room temperature, diluted with MeOH and then concentrated under reduced pressure to give crude product which is chromatographed on silica gel eluting with 4% MeOH / CHCl 3 (+0.1 % NH4 OH) to give the aminoalcohol intermediate [TLC (UV) Rf = 0.25 in 5% MeOH / CHCl 3 (+ 0.5% NH 4 OH); MS (+ ESI) for C 15 H 20 FNO 4 S m / z 330 (M + H) +]. A solution of 0.91 g (2.8 mmol, from a different batch) of the aminoalcohol intermediate in 10 mL of CH 3 CN under N 2 is treated with 0.63 g (3.9 mmol) of 1,1'-carbonyldiimidazole and stirred at room temperature for 24 h. The milky suspension is diluted with CH2 Cl2 and washed with water several times. The washes are extracted with CH 2 Cl 2 and the combined organic extracts are dried (Na 2 SO 4), filtered and concentrated to give the title compound: TLC (UV) Rf = 0.21 in 5% MeOH / CHCl 3 (+ 0.5 % NH4 OH); MS (+ ESI) for C 16 H 18 FNO 5 S m / z 356 (M + H) +. 211 ΡΕ1478629

Step 3: Preparation of (5R) -3- [4- (cis-1-imino-1-oxido-1,1,3,4,5,6-hexahydro-2 H -1,3-pyrazan-4-yl ) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Preparation of the reagent MSH: A solution of ethyl 0-mesitylsulfonylacetohydroxamate (2.53 g, 8.87 mmol) in 7 ml of dioxane is cooled to 0 ° C and treated dropwise with 1.0 ml (11% 6 mmol) of 70% HC104 over ca. of 5 min. The solution is stirred at ice-bath temperature for 7.5 h and then poured into ice-cold water with rapid stirring (35 ml). Stirring was continued for 30 min, and then the white solid was collected by suction filtration through a polypropylene filtration tube, washed several times with ice-cold water and dissolved in ice-cooled CH2 Cl2. This solution is washed twice with cold water and dried rapidly by filtration through a plug of anhydrous K 2 CO 3 to give a stock solution of MSH in CH 2 Cl 2.

The entire MSH stock solution is added directly to 857 mg (2.41 mmol) of (5R) -3- [3-fluoro-4- (cis -tetrahydro-1-oxido-2 H -thiopyran-4- yl) phenyl] -2-oxo-5-oxazolidinecarboxylate (Step 2) suspended in a minimal amount of CH2 Cl2, and the resulting mixture is rapidly stirred at room temperature. After 33 h a thick milky suspension is formed and the reaction appears complete by TLC [(UV) Rf = 0.30 in 5% MeOH / CHCl 3 (+ 0.5% of 212 ΡΕ 1477729 ΝΗ 4) for the sulfoximine intermediate] . The milky suspension is dissolved in MeOH, treated with 10 mL of 2N NH 3 / MeOH and concentrated under reduced pressure until most of CH 2 Cl 2 has been removed. Another 10 ml of 2N NH 3 / MeOH is added and the solution is stirred at room temperature for 2 h. Further NH3 / MeOH reagent is added as needed until all of the ester has been consumed. The solution is concentrated and the crude product is chromatographed on silica gel, eluting with 7.5% MeOH / CHCl 3, and recrystallized from MeOH / CHCl 3 to give the title compound, mp 226-227 ° C; (M + H) +; 1 H NMR (CDCl 3) δ (CDCl 3) δ (CDCl 3) DMSO: δ 7.87 (s, 1H), 7.63 (s, 1H), 7.50 (m, 1H), 7.35 (m, 2H) 5.03 (dd, J1 = 9.5 Hz , J2 = 5.9 Hz, 1H), 4.27 (t, J = 9.3 Hz 1H), 4.01 (dd, J = 9.3 Hz, J2 = 5.9 Hz, 1H) , 3.77 (s, 1H), 3.25-3.80 (m, 3H), 3.06-2.98 (m, 2H), 2.19-2.06 (m, 2H) EXAMPLE 57 (5R) - (-) - 3- [3,5-Difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl) phenyl] -2- oxo-5-oxazolidinecarboxamide

Step 1: Preparation of ethyl 2-cyano-2- (4-nitro-2,6-difluoro-phenyl) propionate 213 ΡΕ1478629

A stirred suspension of anhydrous K 2 CO 3 (79.5 g, 575 mmol) in anhydrous DMF (365 mL) is heated to 150 ° C and treated with ethyl 2-cyanopropionate (71.8 g, 564 mmol) via a addition over 20 min. The reaction is allowed to cool gradually to ambient temperature over 90 min, and then cooled again (to ca. 12 ° C) with a gentle ice bath. The yellow reaction mixture is at this point treated with 3,4,5-tri-fluoronitrobenzene (94.8 g, 535 mmol) via an addition funnel over 20 min. The dark purple reaction mixture is stirred overnight at room temperature. The dark green reaction mixture is then poured into ice / water (950 mL) and made acidic (from pH 11 to pH 5) with 20% v / v / H 2 O 4 SO 4 while stirring vigorously and ensuring ample cooling with ice bath. The mixture is then cooled in a refrigerator for 2 h. The amber-brown liquid is extracted with Et 2 O (1.2 L), taking care to dissolve large clusters of the dark green solid (which count for a significant amount of the product). The ether layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2 x 150 mL), and H2 O (2 x 150 mL), dried over MgSO4, and concentrated under reduced pressure. Trituration (cold hexanes) affords the title compound as a pale tan solid in 77% yield; NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 4.35 (q, 2H), 2.06 (t, 3H), 1.31 (t, 3H).

Step 2: Preparation of 3-methyl-3- (4-amino-2,6-difluoro-phenyl) azetidinone 214 ΡΕ1478629

A solution of ethyl 2-cyano-2- (4-nitro-2,6-difluoro-phenyl) propionate (Step 1, 117.3 g, 413 mmol) in anhydrous THF (1.1 L) is treated with Pd to 10% C (11.73 g) and placed under a hydrogen atmosphere (flask). The reaction mixture is stirred at room temperature for 67 h under hydrogen, then filtered to remove Pd / C and concentrated under reduced pressure to provide the crude nitrile-aniline intermediate (155 g) as an oil dark brown. This crude intermediate is dissolved in absolute EtOH (2.0 L), treated with Nickel Raney (240 g of a 50% slurry in H2 O), and subjected to hydrogenation in a Parr apparatus for 24 h (25-30 psi H2 , room temperature). The reaction mixture is then filtered through Celite (repeated EtOH washes) and concentrated under reduced pressure. Column chromatography &quot; flash &quot; (eluting with 2-3% MeOH / CH 2 Cl 2 and then with 4-5% MeOH (NH 3) / CH 2 Cl 2) affords the uncyclized aminoaniline intermediate (74.2 g, 287 mmol) as an oil amber-pale with 70% yield (two steps). A solution of this aminoaniline (36.1 g, 140 mmol) in THF (800 mL) is added dropwise to a 0 ° C solution of methylmagnesium bromide (220 mL, 3.18M in Et2 O) in THF (1: 32 L). The reaction mixture is then stirred for 22 h with ice-bath quench, and then the reaction contents are poured into ice-cold saturated aqueous NH 4 Cl (1.8 L). The organic and aqueous layers are separated, and the aqueous layer is extracted with THF (3 x 300 mL). All organic layers 215 ΡΕ1478629 are combined and concentrated under reduced pressure. The resulting orange-orange syrup is dissolved in EtOAc (800 mL), washed with H 2 O (200 mL) and brine (200 mL), dried over MgSO 4, and concentrated under reduced pressure. Trituration (Et2 <0 cold) affords the title compound as an orange-pale solid in 74% yield; NMR (400 MHz, DMSO-d 6) δ 7.83 (s, 1H), 6.16 (d, 2H), 5.65 (s, 2H), 3.31 (m, 1H), 3.27 (d, 1H), 1.51 (s, 3H); HMS (ESI) calc. for C10 H10 F2 N20 + Hi 213.0839, found 213.0849.

Step 3: Preparation of methyl 3- (4-amino-2,6-difluorophenyl) -3-methylazetidine-1-carboxylate

A solution of LIAH4 (120.9 mL, 1.0 M in THF) is diluted with THF (117 mL) and cooled to 0 ° C. To this is added a solution of 3-methyl-3- (4-amino-2,6-difluoro-phenyl) azetidinone (Step 2, 8.55 g, 40.3 mmol) in THF (177 mL) of gas. The ice bath is removed and the pale yellow solution is heated to reflux (75Â ° C oil bath) for 22 h during which time the reaction turns to a white suspension. After cooling to room temperature, the mixture is treated successively with H2 O (4. 59 mL), 5N aqueous NaOH (4.13 mL), and H2 O (16.08 mL). The resulting suspension is diluted with CHCl3 and filtered through a pad of Celite, rinsing the Celite with additional CHCl3. Concentration under reduced pressure followed by purification via silica gel chromatography εΕ1478629 (eluting with 5% MeOH (NH)) / CH2 Cl2) affords the intermediate azetidinylaniline (5.80 g, 29.3 mmol) as a white solid. golden syrup in 73% yield. A solution of this intermediate (4.93 g, 24.9 mmol) in CH2 Cl2 (75 mL) is treated with Et3 N (6.93 mL, 49.7 mmol) cooled to 0 ° C and treated with methyl chloroformate ( 2.11 mL, 27.3 mmol) dropwise via syringe. The reaction is stirred for 2 h at ice-bath expiration, and then diluted with CH2 Cl2, washed with H2 O and brine, dried over MgSO4, and concentrated under reduced pressure. Purification of the crude product via silica gel chromatography (eluting with 30% EtOAc / hexane) affords the title compound as a white-yellow deliquescent solid in 79% yield; NMR (400 MHz, DMSO-d6) δ 6.17 (d, 2H), 5.64 (s, 2H), 4.15 (m, 2H), 3.81 (m, 2H), 3.56 ( (s, 3H), 1.50 (s, 3H), HRMS (ESI) calc'd for

C12 H14 F2 N2 O2 + H1 257, 1101, found 257, 1095.

Step 4: Preparation of methyl (5R) -3- [3,5-difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl] -2-oxo-5-oxazolidinecarboxylate

A solution of methyl 3- (4-amino-2,6-difluorophenyl) -3-methylazetidine-1-carboxylate (Step 3, 4.93 g, 19.2 mmol) in CH 3 CN (20 mL) is treated with 2R) -glycidate (1.64 mL, 19.2 mmol) and heated to 50 ° C. To this stirred solution is added LiOTf (3.00 g, 19.2 mmol) in portions, and the reaction mixture is then heated at 217 Ρ AND 147.7929 100 ° C for 4 h. After this time the reaction is allowed to cool to room temperature with stirring overnight. The reaction is then diluted with EtOAc and washed with H2O. The H2 O layer is back-extracted with EtOAc, and the organic layers are combined, dried over MgSO4, and concentrated under reduced pressure. Purification by flash column chromatography &quot; (eluting with 30-40% EtOAc / hexane) affords the hydroxy ester intermediate (4.01 g, 11.2 mmol) as a pale yellow solid in 58% yield. A solution of this hydroxy ester intermediate (3.74 g, 10.4 mmol) in CH 3 CN (33 mL) is treated with CDI (2.03 g, 12.5 mmol) and a single crystal of DMAP. After stirring for 7 days at room temperature, the reaction contents are poured into H 2 O (150 mL). The resulting phase is then extracted with EtOAc (3 x 100 mL), and the combined organic layers are dried over MgSO4 and concentrated under reduced pressure. Purification of the crude product via silica gel chromatography (eluting with 35-45% EtOAc / hexane) affords the title compound as a white solid in 83% yield; 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (d, 2H), 5.37 (dd, 1H), 4.34 (t, 1H), 4.25 (m, 2H), 4.18 (dd, 1H), 3.87 (d, 2H), 3.77 (s, 3H), 3.57 (s, 3H), 1.57 (s, 3H); HMS (ESI) calc. Calc'd for C 17 H 18 F 2 N 2 O 6 + H + 385.1212, found 385.1999.

Step 5: Preparation of (5R) - (-) - 3- [3,5-Difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidine- nocarboxamide 218 ΡΕ1478629

A suspension of methyl (5R) -3- [3,5-difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl] -2-oxo-5-oxazolidinecarboxylate (Step 4, 500 (10 mL) is heated at 50 ° C until complete dissolution is obtained, then cooled to 0 ° C and treated with NH 3 -MeOH (5 mL). (Et2 O) affords the title compound as a white solid in 97% yield; 1 H NMR (400 MHz, DMSO-d6):? ) δ 7.88 (s, 1H), 7.64 (s, 1H), 7.35 (d, 2H), 5.05 (dd, 1H), 4.26 (m, 2H), 4.25 (d, 2H), 3.56 (s, 3H), 1.57 (s, 3H), hMS (ESI) calc'd for C16 H17 F2 N3 O5 + H1 370, 1214, found 370.1206; [Î ±] 25d = -20 (c => DMSO) -4- (1-methoxycarbonyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidine carboxamide

A suspension of methyl (5R) -3- [3,5-difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl] -2-oxo-5-oxazolidinecarboxylate (EXAMPLE 57, Step 4 , 500 mg, 1.30 mmol) in MeOH (10 mL) is heated at 50 ° C until complete dissolution is obtained, then cooled to 0 ° C and treated with methylamine (15 mL, 2.0 M in MeOH) (Et2 O) affords the title compound as a white solid in 90% yield; 1 H NMR (CDCl3) δ 400 MHz, DMSO-d 6) δ 8.41 (d, 1H), 7.35 (d, 2H), 5.09 (dd, 1H), 4.26 (m, 2H), 4.25 (t, 1H), 4.02 (dd, 1H), 3.86 (d, 2H), 3.56 (s, 3H), 2.66 (d, 3H), 1.56 (s, 3H) IEP) calc'd for C 17 H 19 F 2 N 3 O 5 + H 384, 1371, found 384, 1360, [α] 25D = -35 (c 0.90, DMSO). EXAMPLE 59 (5R) -3- (3,4- 4-methyl-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide

2

Step 1: Preparation of 4-methyl-7-amino-2 H -1,4-benzoxazin-3-one To a stirred suspension of 4-methyl-7-nitro-2H-1,4-benzoxazin- 19802239, 2.43 g, 11.67 mmol) in

EtOH (20 mL) and water (10 mL) is added ammonium chloride (6.25 g, 116.70 mmol). To this mixture is added iron (1.95 g, 35.00 mmol) in 3 equal portions. The resulting mixture is heated to 80 ° C for 2 h at which time the reaction is cooled to room temperature followed by addition of CH 2 Cl 2 (100 mL). The resulting mixture is filtered through celite and the filtrate is further diluted with water (100 mL). The organic layer is separated by 220 Ρε1478629 followed by further extraction of the aqueous phase with CH2 Cl2 (3 x 50 mL). The organic phase is combined, dried over Na 2 SO 4 and concentrated under reduced pressure, and the product is purified by silica gel column chromatography (EtOAc) to give the title compound in quantitative yield, m / z 179 , 1 (M + H) +.

Step 2: Preparation of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl) -2- 5-oxazolidinecarboxylic acid To a stirred solution of 4-methyl-7-amino-2 H -1,4-benzoxazin-3-one (Step 1, 7.24 g, 40.63 mmol) in CH 3 CN (75 mL) (6.97 g, 44.69 mmol) followed by methyl (R) -glycidate (4.55 g, 44.69 mmol). The resulting mixture is heated to 50 ° C overnight at which time HPLC indicates complete consumption of the starting material. The reaction is quenched by addition of water (300 mL), EtOAc (500 mL) and brine (50 mL). The organic phase is separated, followed by further extraction of the aqueous phase with EtOAc (3 x 10 mL). The combined organic phase is dried over Na 2 SO 4, filtered and concentrated under reduced pressure to afford crude amino alcohol intermediate which is passed through a short silica gel column (EtOAc) to remove the polar impurities (weight of material : 12.24 g). The product obtained above is dissolved in anhydrous CH 3 CN (100 mL) followed by addition of CDI (19.74, 121.89 mmol, 3 eq, wrt of the above aniline) at room temperature. The resulting reaction mixture is stirred overnight at which time it is diluted with 0.1N HCl (50 mL). The resulting white precipitate is collected by filtration, washed with additional 0.1N HCl (25 mL) and water (100 mL) and dried under high vacuum to give the title compound (7.68 g, 61% for the two steps), MS m / z 307.5 (M + H) +.

Step 3: Preparation of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2'-1,4-benzoxazin-7-yl) -2-oxo-oxazolidine- 5-carboxylic acid (Step 2, 2.41 g, 7.87 mmol) in MeOH (25 mL) is added 2M NH 3 in MeOH (25 mL, 50 mmol). The resulting clear solution becomes cloudy after ~ 10 min. This mixture is stirred for 16 h at which time the reaction is diluted with ether (20 mL) and the resulting white solid filtered off. This white solid is washed with several portions of ether (50 mL) and dried under high vacuum to give the title compound (1.87 g, 81%), NMR (300 MHz, DMSO) δ 7.85 ( 1H), 7.60 (bs, 1H), 7.31-7.14 (m, 3H), 5.00 (dd, 1H), 4.65 (s, 2H), 4.21 (t, 1H), 3.97 (dd, 1H), 3.32 (s, 3H); MS for C 14 H 13 N 3 O 5 m / z 292.5 (M + H) +. EXAMPLE 60 (5R) -N-Methyl-3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide ΡΕ1478629

To a stirred suspension of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo- 5-carboxylic acid (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (5 mL) is added MeNH 2 (5 mL, 10 mmol, 2M solution in MeOH). The resulting solution is stirred for 3 h at ambient temperature time at which time the resulting white precipitate is filtered, washed with more MeOH (5 mL), and dried under high vacuum to give the title compound (153 mg, 77%) as a white solid. %); 1 H NMR (300 MHz, DMSO) δ 8.56 (t, 1H), 7.50 (d, 1H), 7.41-7.33 (m, 2H), 5.23 (dd, (S, 2H), 4.45 (dd, 1H), 4.15 (dd, 1H), 3.45 (s, 3H), 2.84 (d, 2H), MS for C14 H15 N3 O5m / z 306 EXAMPLE 61 (5R) -N- (2-Fluoroethyl) -3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin- 7-yl) -2-oxo-5-oxazolidinecarboxamide

To a stirred suspension of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo- 5-carboxylic acid (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (7.5 mL) is added FCH2 CH2 NH2 · HCl (325 mg, 3.25 mmol). To this resulting suspension is added triethylamine (453 μl, 3.25 mmol), and the solution is heated to 55 ° C for 5 h followed by stirring for 16 h at room temperature. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is purified by silica gel column chromatography (eluent: EtOAc) to give the title compound (153 mg, 63% ); 1 H NMR (300 MHz, dmso, δ 8.68 (t, 1H), 7.30 (d, 1H), 7.22-7.14 (m, 2H), 5.08 (dd, 1H) , 4.54 (dd, 1H), 4.38 (t, 1H), 4.26 (t, 1H), 3.45 (s, 3H), 3.96 (s, dd, 1H), 3.50-3.35 (m, 5H), MS for C15 H16 FN3 O5 m / z 338.5 (M + H) + Example 62 (5R) -3- (3,4- -4-methyl-3-oxo-2 H -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 2-amino-5-nitrobenzenethiol To a stirred solution of 6-nitrobenzothiazole (30 g, 0.1665 mol) in ethanol (500 mL) is added 100% hydrazine hydrate (60.2 mL, 1 , 931 mol). The mixture is refluxed for 2 h at which time the solution turns red. The reaction is quenched by the addition of conc. cooled with ice until the red color disappears. The resulting solid is filtered, washed with water (25 mL) and dried under high vacuum to give the title compound as a yellow solid (28.96 g, 84%), MS m / z 171 , 5 (M + H) +.

To a stirred suspension of 2-amino-5-nitrobenzenethiol (Step 1, 29 gm) in dichloromethane , 139.8 mmol) and potassium carbonate (115.93 g, 838.8 mmol) in dry DMF (150 mL) is added methyl bromoacetate (15.88 mL, 167.8 mmol). The reaction mixture is heated at 50 ° C for 16 h at which time the reaction is quenched with ice and water (50 mL). The precipitate is filtered and dried under high vacuum to give the title compound as a yellow solid (21.69 g, 74%), MS m / z 211.5 (M + H) +.

To a stirred suspension of 3,4-dihydro-7-nitro-2H-imidazole-3-carboxylic acid -1,2-benzothiazin-3-one (Step 2, 4.7 g, 22.3 mmol) and potassium carbonate (3.70 g, 26.8 mmol) in dry DMF (40 mL) in an ice bath is added iodomethane (4.16 mL, 66.8 mmol). The reaction mixture is removed from the ice bath and heated at 50 ° C for 1-2 h. The resulting mixture is allowed to cool. Water (35 mL) and ice are added and the precipitate is separated by filtration and washed with water (10 mL). The resulting solid is dried under high vacuum to give the title compound as a yellow solid (4.5 g, 90%), MS m / z 225.5 (M + H) +. 225 ΡΕ1478629

To a stirred solution of 3,4-dihydro-4-methyl-7-methyl-7-amino-2H-1,4-benzothiazin- 1,4-benzothiazin-3-one (4.50 g, 20.07 mmol) in EtOH (100 mL) and water (50 mL) is added ammonium chloride (10.76 g, 200 mmol) , 7 mmol). To this mixture is added iron (3.37 g, 60.21 mmol) in 3 equal portions. The resulting mixture is heated to 80 ° C for 2 h at which time the reaction is cooled to room temperature. This mixture is filtered and the filtrate is concentrated under reduced pressure and extracted with EtOAc (3 x 50 mL). The organic phase is washed with water and brine, dried over MgSO 4, and concentrated under reduced pressure to give the title compound (for reference DE 19802239) as a dark brown oil (3.60 g, 93%). MS) m / z 195.5 (M + H) +.

Step 5: Preparation of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2 H -1,4-benzothiazin-7-yl) -2-oxo- 5-oxazolidinecarboxylic acid To a stirred solution of 3,4-dihydro-4-methyl-7-amino-2H-1,4-benzothiazin-3-one (Step 4, 3.60 g, 18.54 mmol) in CH 3 CN (15 mL) is added LiOTf (3.47 g, 22.24 mmol) and methyl (R) -glycidate (1.9 mL, 22.24 mmol). The resulting mixture is stirred at 100 ° C for 4 h at 226 ° F and 147 ° C whereupon the reaction is cooled to room temperature and worked up in CH2 Cl2 (3 x 60 mL) and water (60 mL). The combined organic phase is washed with brine, dried over MgSO 4, and concentrated under reduced pressure to give a dark oil which is purified by column chromatography (25% acetone / CH 2 Cl 2) to give the intermediate amino alcohol as a dark yellow oil (3.39 g, 62%, MS m / z 297.5 (M + H) +). To a stirred solution of this intermediate (3.39 g, 11.44 mmol) in dry CH 3 CN (15 mL) is added CDI (5.56 g, 34.32 mmol). The resulting mixture is heated at 50 ° C for 30 min at which time the reaction is cooled to room temperature and concentrated under reduced pressure. The crude product is purified by column chromatography (100% EtOAc) to give the title compound as a yellowish white solid (3.14 g, 85%), MS m / z 323.5 ( M + H) +.

Step 6: Preparation of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2 H -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl) -2-oxo- 5-oxazolidinecarboxylic acid (Step 5, 200 mg, 0.6205 mmol) in MeOH (3 mL) is added a 2.0M solution of ammonia in MeOH (2.0 mL). This mixture is stirred for 3 h at which time the reaction is concentrated under reduced pressure, washed with ethyl ether (6 mL) and filtered to give the title compound as a white solid (108 mg , 57%), 1 H NMR (300 MHz, DMSO) δ 7.86 (s, 1H), 7.63 (d, 2H), 7.47 (dd, 1H), 7.27 (d, (S, 2H), 3.32 (s, 3H), MS for C 13 H 43 N 3 O 4 S • m / z EXAMPLE 63 (5R) -N-Methyl-3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl ) -2-oxo-5-oxazolidinecarboxamide

To a stirred suspension of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl) -2- oxo-5-oxazolidinecarboxylic acid (EXAMPLE 62, Step 5, 200 mg, 0.6205 mmol) in MeOH (3 mL) is added a 2.0M solution of methylamine in MeOH (2.0 mL). This mixture is stirred for 30 min at which time the reaction is concentrated under reduced pressure, washed with ethyl ether (6 mL) and filtered to give the title compound as a white solid (190 mg, 95%). %), 1H NMR (300 MHz, DMSO) δ 8.38 (d, 1H), 7.63 (d, 1H), 7.46 (dd, 1H), 7.27 (d, 1H), 5.05 (dd, 1H), 3.52 (s, 2H), 3.32 (s, 3H), 2.65 (d, 3H) (5R) -3- [3-Fluoro-4- (5-oxo-5,6-dihydro-4 H - [1 (S) -hydroxy- , 3,4] thiadiazin-2-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide 228 ΡΕ1478629

(I.e.

N, N-Diisopropylethylamine hydrochloride (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoyl) hydrazinecarboxylic acid tert-butyl ester Step 1: Preparation of N '- (2-fluoro- (5 g, 0.027 mol) and O- (7-azabenzotriazol-1-yl) -N, N ', N', N'-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml ) and the mixture stirred at room temperature for 20 minutes. Tert-butyl carbobate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, well washed with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M + H] + = 300.

Step 2: Preparation of N '- (2-fluoro-4-nitro-thiobenzoyl) hydrazinecarboxylic acid tert -butyl ester N' - (2-fluoro-4-nitro-benzoyl) hydrazinecarboxylic acid tert- Step 1, 2.32 g, 7.75 mmol) and Lawesson's Reagent (2.35 g, 5.81 mmol) in dioxane (50 mL) are heated at 85 ° C overnight. The mixture is evaporated in vacuo and the residue purified by flash column chromatography &quot; (dichloromethane at 229Â ° C-147.792929 / hexane) to give the title compound as an orange-brilliant solid (2.02 g, 82%), [M + H] + = 316.

Step 3: Preparation of [(tert-butoxycarbonylhydrazono) - (2-fluoro-4-nitro-phenyl) methylsulfanyl] acetic acid methyl ester

Triethylamine (1.33 ml, 9.57 mmol) is added dropwise at room temperature to N '- (2-fluoro-4-nitro-thiobenzoyl) hydrazinecarboxylic acid tert-butyl ester (Step 2, 2 (0.633 mL, 6.69 mmol) in DMF (20 mL) was added dropwise. The mixture is stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue is purified by flash column chromatography &quot; (50% ethyl acetate / hexane) to give the title compound as an oil (2.20 g, 86%), [M + H] + = 388.

Step 4: Preparation of 2- (2-fluoro-4-nitrophenyl) -4H- [1,3,4] thiadiazin-5-one [(tert-butoxycarbonylhydrazono) - (2-fluoro- 4-nitrophenyl) methylsulfanyl] acetic acid (Step 3, 2.00 g, 5.16 mmol) is dissolved in 20% trifluoroacetic acid in dichloromethane and stirred at room temperature for 45 minutes. The reaction mixture is evaporated in vacuo to give the title compound as a yellow solid (1.30 g, 99%), [M + H] + = 256. 230 ΡΕ1478629

Step 5: Preparation of 2- (4-amino-2-fluorophenyl) -4H- [1,3,4] thiadiazin-5-one 2- (2-Fluoro-4-nitrophenyl) -4H- [1,3 , 4] thiadiazin-5-one (Step 4.0, 0.964 g, 0.00378 mol) is heated in ethanol (20 ml) until dissolved. Water (10 ml) and ammonium chloride (2.02 g, 0.0378 mol) are added and the mixture is heated to 90øC. Iron powder (0.84 g, 0.0151 mol) is added in portions and the mixture stirred and heated for 30 minutes. The reaction is cooled and dichloromethane (100 ml) is added. The mixture is filtered and the organic layer separated, washed with brine, dried (MgSO4) and evaporated to give the title compound as a yellow solid (0.78 g, 92%), [M + H ] + = 226.

Step 6: Preparation of (5R) -3- [3-fluoro-4- (5-oxo-5,6-dihydro-4H- [1,3,4] thiadiazin-2-yl ) phenyl] -2-oxo-5-oxazolidinecarboxylic acid 2- (4-Amino-2-fluorophenyl) -4H- [1,3,4] thiadiazin-5-one (Step 5, 0.71 g, 3.15 (0.91 g, 6.30 mmol) and lithium trifluoromethanesulfonate (0.74 g, 4.73 mmol) in acetonitrile (10 mL) are heated at 90 ° C of a day to the next. The reaction is concentrated and the residue diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography &quot; (50% ethyl acetate / hexane) to afford the aminoalcohol intermediate as an oil (0.99 g, 85%, MS (m / z): [M + H] + = 370) . Phosgene (20% solution in toluene, 0.89 mL, 1.68 mmol) at 0 ° C is added dropwise to a portion of this intermediate (0.516 g, 1.40 mmol) and triethylamine (0.29 mL, 2.10 mmol) in dichloromethane (10 mL). The mixture is allowed to warm to room temperature and stirred for an additional hour. The reaction is washed with 2N aqueous hydrochloric acid and brine, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography &quot; (50% ethyl acetate / hexane) to give the title compound as a white solid (0.33 g, 60%); MS (m / z): [M + H] + = 396.

Step 7: Preparation of (5R) -3- [3-fluoro-4- (5-oxo-5,6-dihydro-4 H - [1,3,4] thiadiazin-2-yl) phenyl] - 2-oxo-5-oxazolidinecarboxamide 3- [3-Fluoro-4- (5-oxo-5,6-dihydro-4H- [1,3,4] thiadiazin-2-yl ) phenyl] -2-oxo-5-oxazolidinecarboxylic acid (Step 6, 0.300 g, 0.758 mmol) is dissolved in 2M ammonia solution in methanol (8 ml) and stirred overnight at room temperature. The reaction is concentrated in vacuo and purified by PTLC (10% methanol / CH 2 Cl 2) to give the title compound as a white solid (0.22 g, 87%), mp 249-251 ° W; 1 H NMR (300 MHz, CDCl 3) δ 3.59 (s, 2H), 4.04 (dd, 1H), 4.30 (t, 1H), 5.05 (dd, 1H), 7.49-7 , 72 (m, 4H), 7.88 (bs, 1H), 11.63 (s, 1H); MS (m / z) for C 13 H 11 FN 4 O 4 S: [M + H] + = 339. EXAMPLE 65 (5R) -3- [4- (1,1-Dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl) -3,5-difluorophenyl] -2- oxo-5-oxazolidinecarboxamide

NH2

Step 1: Preparation of methyl (2R) -3 - {[4- (1,1-dioxidothiomorpholin-4-yl) -3,5-difluorophenyl] amino} -2-hydroxypropanoate

A solution of 4- (1,1-dioxidothiomorpholin-4-yl) -3,5-difluoroaniline (EXAMPLE 15, Step 3, 1.30 g, 5.0 mmol) in acetonitrile (7.5 mL) is treated with (0.60 g, 5.0 mmol) and methyl (2R) -2,3-epoxypropanoate (0.51 g, 0.46 mL, 5.0 mmol) and heated to 70 ° C for 2 hours. H. At this point an additional amount (1.5 mmol each) of the two reactants is added and the mixture stirred for another 7 h at 70øC. The reaction mixture is then cooled to room temperature, concentrated, and purified by column chromatography (50-60% ethyl acetate-hexane) to provide the title compound (1.03 g, NMR (300 MHz, CDCl 3): δ 3.04 (d, 1H), 3.15 (m, 4H), (M, 4H), 3.83 (s, 3H), 4.20 (t, 1H), 4.40 (m, 1H), 6.17 (d, 2H).

Step 2: Preparation of methyl (5R) -3- [4- (1,1-dioxidothiomorpholin-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxylate 233 ΡΕ1478629 methyl

A solution of methyl (2R) -3 - {[4- (1,1-dioxidothiomorpholin-4-yl) -3,5-difluorophenyl] amino} -2-hydroxypropanoate (Step 1, 1.02 g, 2.90 mmol) in CH2 Cl2 (25 mL) and triethylamine (1.0 g, 1.5 mL, 10.5 mmol) is cooled to 0 ° C and treated with phosgene (1.94 mL of a 20% in toluene, 3.6 mmol). After stirring at room temperature for one hour, the reaction mixture is diluted with CH 2 Cl 2 and washed with dilute NaHCO 3, brine, and dried (MgSO 4), filtered and concentrated. Chromatography on silica gel (10% acetonitrile-dichloromethane) affords the title compound (0.91 g, 83%), MS (m / z): [M + H] + = 311; Δ NMR (300 MHz, CDCl3): δ 3.16-3.20 (m, 4H) 3.64 (m, 4H), 3.88 (s, 3H), 4.06-4.11 (m, 1H), 4.23 (t 1H), 5.06-5.11 (m, 1H), 7.16 (d, 2H).

Step 3: Preparation of (5R) -3- [4- (1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl) -3,5-difluorophenyl ] -2-oxo-5-oxazolidinecarboxylate

A solution of methyl (5R) -3- [4- (1,1-dioxidothiomorpholin-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxylate (Step 2, 0.73 g, Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.27 g, 5.6 mmol) in dioxane (9 mL) is heated to 100 ° C for two days. The solution is cooled and treated with 20 mL of 10% aqueous Na2 SO4 and stirred for 30 minutes. The solution is then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated NaHCO3 and brine and dried (MgSO4), filtered and concentrated. The crude residue is purified by column chromatography (0-5% ethyl dichloromethane) to provide the title compound (0.28 g, 38%); 1 H NMR (300 MHz, CDCl 3): δ 3.31-3.35 (m, 2H), 3.89 (s, 3H), 4.00-4.15 (m, 3H), 4.25 (t , 5.11 (m, 1H), 5.45 (d, 1H), 6.54 (d, 1H), 7.29 (d, 2H).

Step 4: Preparation of (5R) -3- [4- (1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide

A solution of (5R) -3- [4- (1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl) -3,5-difluorophenyl] -2-oxo (3 mL, 0.090 g, 0.23 mmol) in methanol (2 mL) is treated with a solution of ammonia in methanol (2 mL of a 2.0 M solution) . The mixture is stirred for 1.5 h and concentrated. The residual solids are washed with methanol to provide 75 mg (86%) of the title compound as a white solid, MS (m / z) for C 14 H 13 F 2 N 3 O 5 S: [M + H] + = 374; Δ NMR (300 MHz, d 6 -DMSO): δ 3.33-3.39 (m, 2H), 3.99-4.06 (m, 3H), 4.26 (t, 1H), 5.04 (D, 1H), 6.93 (d, 1H), 7.50 (d, 2H), 7.65 (s, 1H), 7.90 (d, s, 1H). EXAMPLE 66 (5R) -3- [4- (2,5-Dihydro-1H-pyrrol-1-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide 235 ΡΕ1478629

Step 1: Preparation of 1- (2,6-difluoro-4-nitrophenyl) -2,5-dihydro-1 H -pyrrole

Trifluoronitrobenzene (5 g, 28.2 mmol) and 3-pyrroline (1.95 g, 28.2 mmol) are taken up in CH 3 CN (70.0 mL) and diisopropylethylamine (5.4 mL, 31.02 mmol) and heated to 60 ° C for 4 h. The reaction mixture is cooled to room temperature, dissolved in ethyl acetate and washed with 0.1N HCl, satd NaHCO3, water, and brine, and dried (MgSO4), filtered and concentrated to provide the title compound. (300 g, CDCl3): δ 4.64 (s, 4H), 5.85 (s, 2H), 7.71 (d, 2H).

Step 2: Preparation of 4- (2,5-dihydro-1H-pyrrol-1-yl) -3,5-difluoroaniline

Ammonium chloride (1.18 g, 22.1 mmol) is added to a mixture of 1- (2,6-difluoro-4-nitrophenyl) -2,5-dihydro-1H-pyrrole (Step 1.0 , 5 g, 2.21 mmol) dissolved in EtOH / water (2: 1, 18.0 mL) and heated to reflux. Iron powder (0.37 g, 6.63 mmol) is added portionwise over one hour. After reflux for another 45 min, the reaction mixture is cooled, filtered, and extracted three times with dichloromethane. The organic layers are washed with brine, dried (MgSO4) and concentrated to provide the title compound (0.43 g,> 95%), MS (m / z): [M + H] + = 197; 1 H NMR (300 MHz, CDCl 3): δ 3.63 (bs, 2H), 4.10 (s, 4H), 5.84 (s, 2H), 6.17 (d, 2H).

Step 3: Preparation of methyl (2R) -3 - {[4- (2,5-dihydro-1 H -pyrrol-1-yl) -3,5-difluorophenyl] amino-2-hydroxypropanoate ) -2,3-epoxypropanoate (0.34 g, 3.3 mmol) and lithium triflate (0.52 g, 3.3 mmol) are added to a solution of 4- (2,5- dihydro-1H-pyrrol-1-yl) -3,5-difluoroaniline (Step 2, 0.43 g, 2.2 mmol) in acetonitrile (7.5 mL), and the mixture is heated to 60 ° C for 16 hours. H. The reaction mixture is then concentrated and the residue purified by pCCF (50% EtOAc / hexanes) to provide the title compound (0.30 g, 46%), MS (m / z): [M + H] + = 299.5; Δ NMR (300 MHz, CDCl3): δ 3.34-3.41 (m, 2H), 3.77 (s, 3H), 4.08 (s, 4H), 4.35-4.37 , 1H), 5.82 (s, 2H), 6.16 (d, 2H).

Step 4: Preparation of methyl (5R) -3- [4- (2,5-dihydro-1H-pyrrol-1-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxylate

A solution of methyl (2R) -3 - {[4- (2,5-dihydro-1 H -pyrrol-1-yl) -3,5-difluorophenyl] amino} -2-hydroxypropanoate ( Step 3, 0.3 g, 1.0 mmol) in acetonitrile (10.0 mL) is treated with 1,1'-carbonyldiimidazole (0.33 g, 2.0 mmol) and stirred at room temperature for 16 h. The reaction mixture is concentrated and the residue taken up in ethyl acetate. This organic solution is washed with dilute citric acid ΡΕ1478629, water, and brine and dried (MgSO4). Purification by pCCF (50% EtOAc / hexanes) affords the title compound (0.15 g, 46%), MS (m / z): [M + H] + = 325.5; Δ NMR (300 MHz, CDCl3): δ 3.88 (s, 3H), 4.03-4.08 (m, 1H), 4.20 (t, 1H), 4.37 (s, 4H), 5. 03-5.08 (m, 1H), 5.87 (s, 2H), 7.06 (d, 2H).

Step 5: Preparation of (5R) -3- [4- (2,5-dihydro-1H-pyrrol-1-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide

A solution of methyl (5R) -3- [4- (2,5-dihydro-1 H -pyrrol-1-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidine-5-carboxylate (Step 4, 0.09 g, 0.28 mmol) in 2.0M ammonia in MeOH (2.8 mL) is heated to 55 ° C for 4 h. The reaction mixture is cooled, concentrated and the residue purified by means of pCCF (5% MeOH / CH 2 Cl 2) to give

title compound (50 mg, 58%); MS for C 14 H 13 F 2 N 3 O 3 MS m / z 310.5 (M + H) +; Δ NMR (300 MHz, d6-DMSO): δ 3.93-3.98 (m, 1H), 4.17-4.25 (m, 5H), 4.97-5.02 (m, 1H) , 5.93 (s, 2H), 7.27 (d, 2H), 7.61 (s, 1H), 7.85 (s, 1H). EXAMPLE 67 (5R) -3- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3,4-dihydro-17-quinolin-2-yl) -3,4-dihydro-2 (1H) -quinolinone (1.0 g, 6.70 mmol ) is dissolved in 20 mL of concentrated sulfuric acid at -10 ° C, and then 5 mL of water is slowly added to the solution. After 5 minutes, 61% nitric acid (0.5 mL, 6.70 mmol) is added dropwise to the solution. The reaction mixture changes from yellow to dark red, and eventually solidifies. After 1 hour, water (50 mL) is slowly added at -10 ° C and precipitate appears. The solution is poured into a separatory funnel, extracted with ethyl acetate (20 mL x 2) and washed with brine (20 mL). The organic layers are collected and dried over MgSO4. The solvent is removed and the title compound is obtained as a pale yellow solid (1.0 g, 76%); NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 8.08-8.01 (m, 2H), 6.96 (d, 1H), 2.98 (t, 2H) 49 (dd, 2H).

Step 2: Preparation of 1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one To a stirred suspension of 6-nitro-3,4-dihydro-1 H -quinolin-2 (855 mg, 1.2 equiv.) in DMF (3.0 mL) was added followed by Mel (0.64 mL, 2.0 equiv) . The resulting solution is stirred overnight at room temperature. Water (20 mL) is then added and the reaction mixture is extracted with ethyl acetate (20 mL x 2) and washed with brine (20 mL). The organic layers are collected and dried over MgSO4. The solvent is removed to give the title compound as a yellow solid (956 mg, 90%). 1H NMR (DMSO-d6):? NMR (300 MHz, DMSO) δ 8.16-7.26 (m, 3H), 3.30 (s, 3H), 3.00 (t, 2H), 2.61 (m, 2H).

Step 3: Preparation of 6-amino-1-methyl-3,4-dihydro-1 H -quinolin-2-one To a stirred suspension of 1-methyl-6-nitro-3,4-dihydro- -quinolin-2-one (Step 2, 1.04 g, 5.05 mmol) in

EtOH (10 mL) and water (5 mL) is added ammonium chloride (2.70 g, 10.0 equiv). To this mixture is added iron powder (0.85 g, 3.0 equiv) in 3 portions. The resulting mixture is heated at reflux for 2 h and then cooled to room temperature. The resulting mixture is filtered through celite and the filtrate is further diluted with water (100 mL). The filtrate is extracted with ethyl acetate (2 x 50 mL) and washed with brine (100 mL). The organic layers are combined, dried over MgSO 4 and concentrated under reduced pressure to afford the title compound as a yellow solid (0.86 g, 97%), MS (m / z): 177.5 [ M + H] +.

Step 4: Preparation of 3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxylic acid methyl ester To a stirred solution of 6-amino-1-methyl-3,4-dihydro-1 H -quinolin-2-one (Step 3, 0.86 g, 4.91 mmol) in acetonitrile (5 mL) is added lithium triflate , 77 g, 240 Ρ AND 147.7929, 4.91 mmol) followed by methyl (R) -glycidate (0.42 mL, 4.91 mmol). The resulting mixture is heated at 100 ° C for 3 h, at which time HPLC indicates complete consumption of the starting material. The reaction is quenched by addition of water (50 mL), and the reaction mixture is extracted with dichloromethane (50 mL x 2). The combined organic layer is washed with brine (100 mL), dried over MgSO 4 and concentrated under reduced pressure, and the resulting crude oil is purified by silica gel chromatography (20% acetone / CH 2 Cl 2) to give the amino alcohol intermediate as a yellow solid (0.72 g). This intermediate is dissolved in anhydrous acetonitrile (3 mL) followed by addition of CDI (0.95 g, 2.25 equiv) at room temperature. The resulting reaction mixture is stirred for 1 hour at room temperature. The solvent is removed and the residue is purified by silica gel chromatography (100% EtOAc) to give the title compound as a white solid (0.60 g, 76%), MS ( m / z): 305.5 [M + H] +.

Step 5: Preparation of (5R) -3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide To a stirred solution of 3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 4, 150 mg, 49 mmol)

MeOH (1 mL) is added 2.0M NH 3 in MeOH (1 mL, 2.0 mmol). The reaction mixture is then heated to 50-60 ° C until all the solid disappears. The solvent is removed and the residue is dissolved in 20% MeOH / CH 2 Cl 2 and purified by silica gel chromatography (10% MeOH / CH 2 Cl 2) to give the title compound as a solid NMR (300 MHz, DMSO) δ 7.85 (bs, 1H), 7.60 (bs, 1H), 7.45-7.08 (m, 3H), 5.01 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s, 3H), 2.86 (t, 2H), 2.50 (5R) -N-Methyl-3- (1-methyl-2-oxo-1,2,3,4-tetrahydro-1H- -hydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide

To a stirred solution of 3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 67, 4,150 mg, 0.49 mmol) in MeOH (2 mL) is added MeNH2 (2 mL, 4.0 mmol, 2M solution in MeOH). The reaction mixture is then stirred for 30 minutes at room temperature. The solvent is removed and the residue is washed with ether to give the title compound as a white solid (120 mg, 80%), NMR (300 MHz, DMSO) δ 8.37 (d, 1H) (S, 3H), 7.44 (s, 3H), 7.44 (s, 1H), 7.74-7.07 (m, 3H), 5.04 (dd, 1H), 4.25 (t, 1H) 2H), 2.86 (t, 2H), 2.65 (d, 3H), 2.50 (m, 2H), MS for C15 H17 N3 O4 m / z 304.5 (M + H) +. - [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) -242 ΡΕ1478629 3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 1- (2-fluoro-4-nitrophenyl) piperidin-4-one To a stirred solution of 4-piperidone monohydrate hydrochloride (258.7 g, 1.68 mol) propyleneamine (590 ml, 3.39 mol) in acetonitrile (2.5 liters) is added 3,4-difluoronitrobenzene (186.3 ml, 1.68 mol). The mixture is heated to 80 ° C and stirred overnight. The solvent is cooled to room temperature and removed under reduced pressure. The residue is partitioned between ethyl acetate and 10% aqueous HCl (1.20 liters each). The layers are shaken, and the organic layer is separated and washed with 10% HCl and brine (800 ml each). The organic layer is dried over MgSO4 and filtered. As the solvent is removed under reduced pressure a solid begins to separate by precipitation (~1 / 4 volume). The resulting slurry is cooled to 0-5 ° C and filtered to provide 333.7 g of the title compound, 1 H NMR (400 MHz, CDCl 3) δ 2.65 (m, 4H), 3.65 (m, 4H), 6.98 (m, 1H), 7.26 (s, 1H), 8.00 (m, 1H).

Step 2: Preparation of 1- (2-fluoro-4-nitrophenyl) -4 - [(tri-Î ± -DELTA3,786,29 methylsilyl) oxy] -1,2,3,6-tetrahydropyridine To a stirred solution of 1- (2 4-one (Step 1, 250 g, 1.05 mol) and triethylamine (223 g, 2.20 mol) in toluene (4.2 liters) at 0 ° C is slowly added trimethylsilyl trifluoromethanesulfonate (TMS-OTF, 280 g, 1.26 mol) via an addition funnel. Stirring is continued for 30 min and the mixture is allowed to warm to room temperature. Water (5 liters) is added and the aqueous layer is extracted with EtOAc (3 x 500 ml). The organic extracts are combined, dried over MgSO4 and the solvent removed under reduced pressure. Hexane (4 x 500 ml) is added and the solvent is removed under reduced pressure. In the fourth co-distillation, a slurry is formed (-300 ml). The mixture is cooled to 0 ° C and the solids filtered. The filtrate is concentrated to a slurry, cooled and filtered (2nd crop). The solids are combined to give 273.7 g (84%) of the title compound as a yellow solid, 1 H NMR (CDCl 3) δ 0.21 (s, 9 H), 2.20 (s g 2H), 3.62 (bs, 2H), 4.89 (bs, 1H), 6.65 (t, 1H), 7.67 (d, 1H), 3.52 (bs, 2H) ), 7.73 (d, 1H).

Step 3: Preparation of 1- (2-fluoro-4-nitrophenyl) -2,3-dihydro-1H-pyridin-4-one To a stirred solution of 1- (2-fluoro-4-nitro-phenyl ) -4 - [(trimethylsilyl) oxy] -1,2,3,6-tetrahydropyridine (Step 2, 100.0 g, 322 mmol) and allyl methyl carbonate (43.6 g, 386 mmol) in DMSO (625 ml) at room temperature 244 ΡΕ 1477729 is added Pd (0Ac) 2 (7.20 g, 32 mmol). The resulting solution is stirred under N 2 at room temperature overnight. H2O (1 liter) is added and the solvent is allowed to cool to room temperature. The aqueous layer is extracted with EtOAc (2 x 800 mL), and the combined organic layers are washed with brine (800 mL) and dried over MgSO 4. The solvent is removed and the residue recrystallized from EtOAc / MTBE to provide 53.6 g (70%) of the title compound as a yellow solid.1 H NMR (CDCl3) δ 2.71 ( m, 2H), 4.06 (m, 2H), 5.41 (d, 1H), 7.25 (m, 1H), 7.35 (d, 1H), 8.08 (m, 2H).

Step 4: Preparation of 1- (4-amino-2-fluorophenyl) -2,3-dihydro-1 H -pyridin-4-one

In a 500 ml Parr bottle, 1- (2-fluoro-4-nitrophenyl) -2,3-dihydro-1H-pyridin-4-one (Step 3, 35 g, 148.3 mmol), Pd / CaC03 (3.5 g, 10% by weight) and acetic acid (17 ml, 297 mmol) are combined in THF (350 ml). The mixture is hydrogenated at 40øC under 15 psi of hydrogen for 6 h, at which time the reaction is complete by HPLC. The reaction mixture is filtered through a GF / F filter and the catalyst cake washed with THF (350 mL). The filtrate is partitioned between 500 ml of NaHCO3 and 500 ml of ethyl acetate. The organic layer is washed again with 500 ml of NaHCO3. The organic layer is separated and dried over MgSO4. The mixture is filtered, and the filtrate is concentrated under reduced pressure to provide 29.0 g (95% recovery) of the title compound, MS (ESI-) 245 Ρ AND I-1471729 to C 11 H 11 FN 2 O m / z 205.0 (MH) ; Δ NMR (MeOD) δ 7.37 (d 1H), 7.02 (t, 1H), 6.47 (m, 3H), 5.07 (d, 1H), 3.84 (t. , Δ (t, 1H).

Step 5: Preparation of 3- [3-fluoro-4- (4-oxo-3,4-dihydro-2 H -pyridin-1-yl) phenylamino] -2 (R) -hydroxypropionic acid ethyl ester

A solution of 1- (4-amino-2-fluorophenyl) -2,3-dihydro-1 H -pyridin-4-one (Step 4, 0.412 g, 2.0 mmol) and oxirane- 2 (R) -carboxylic acid (0.394 g, 3.4 mmol) with lithium triflate (0.360 g, 3.0 mmol) in dry acetonitrile (5.0 mL) is heated at 50-60 ° C for 24 h. The volatiles are removed in vacuo, and the crude material purified by flash chromatography &quot; on silica gel (eluent: 5% acetone in CH 2 Cl 2) to provide the title compound (290 mg, 45%) as a viscous yellow oil, MS (m / z): 323 [M + H] ] +.

Step 6: Preparation of 5 (R) -3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide CDI (162.0 mg, 1.0 mmol) is added with stirring to a solution of 3- [3-fluoro-4- (4-oxo-3,4-dihydro-2 H -pyridine yl) phenylamino] -2 (R) -hydroxypropionic acid (Step 5, 146.0 mg, 0.45 mmol) in acetonitrile (4.0 mL), and the mixture is stirred at room temperature for 24 h. day to the next. The solvent is removed in vacuo, and the residue partitioned between EtOAc (30 mL) and citric acid aq. to 3% (30 mL). The aqueous layer is extracted with

EtOAc (2 x 30 mL), and the combined organic layers are washed with water and brine and dried (MgSO4). EtOAc is removed in vacuo to provide 3- [3-fluoro-4- (4-oxo-3,4-dihydro-2 H -pyridin-1-yl) phenyl] -2- oxo-5-oxazolidinecarboxylic acid which is used in the next step without further purification (MS (m / z): 349 [M + H] +). The ester intermediate is taken up in 2M methanolic ammonia (8.0 mL, 16.0 mmol), and the resulting solution is heated in a closed vial at 60 ° C for 1 h. The volatiles are removed in vacuo, and the crude material purified by silica gel chromatography (eluent: 2% MeOH in CH 2 Cl 2) to afford the title compound (55.0 mg, 38% for the two steps) as white crystals, MS for C 15 H 14 FN 3 O 4 m / z 322 (M + H) +; Δ NMR (CD3CN): δ 2.51 (m, 2H), 3.89 (m, 2H), 4.05 (m, 1H), 4.24 (dd, 1H), 4.97 1H), 5.03 (d, 1H), 6.18 (bs, 1H), 6.72 (bs, 1H), 7.20-7.40 (m, 3H), 7.57 (d, 1H). EXAMPLE 70 (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

To a stirred solution of 3- [4- (4-oxo-3,4-dihydro-2 H -pyridin-1-yl) -3-fluorophenyl] -2-oxo- 5-oxazolidinecarboxylic acid (EXAMPLE 69, within Step 6, 120 mg, 0.34 mmol) in MeOH (1 mL) is added MeNH 2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is stirred for 1 h at room temperature. The solvent is removed and the residue is purified by column chromatography (10% MeOH / CH 2 Cl 2) to give the title compound as a pale yellow solid (60 mg, 52%), 1 H NMR ( 300 MHz, DMSO) δ 8.39 (m, 1H), 7.65-7.38 (m, 4H), 5.06 (dd, J t-14.98 (d, 1H), 4.27 (m, t, 1H), 4.02 (dd, J = 3.87 (t, 2H), 2.65 (d, 3H), MS for C16H16FN3O4 m / z 334.5 (M + H) +. (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

To a stirred solution of 3- [4- (4-oxo-3,4-dihydro-2'-pyridin-1-yl) -3-fluorophenyl] -2-oxo-5- oxazolidinecarboxylic acid (EXAMPLE 69, within Step 6, 108 mg, 0.31 mmol) in MeOH (1 mL) is added EtNH2 (2 mL, 4.0 mmol, 2.0M solution in THF). The reaction mixture is stirred for 1 h at room temperature. The solvent is removed and the residue is purified by column chromatography (10% MeOH / CH 2 Cl 2) to give the title compound 248 ΡΕ78686292929 sob sob sob as a pale yellow solid

NMR (300 MHz, DMSO) δ 8.46 (t, 1H), 7.65-7.38 (m, 4H), 5.05 (dd, 1H), 4.99 (d, 1H), 4.27 (t, 1H), 4.01 (dd, 1H), 3.87 (t, 2H), 3.20-3.10 (m, 2H), 1.beta. (3R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl] -1H-indol- ) phenyl] -2-oxo-5-oxazolidinecarboxamide

Hik

Step 1: Preparation of 1- (4-nitrophenyl) piperidin-4-one The title compound is prepared following the method described in EXAMPLE 69, Step 1 using 4-fluoronitrobenzene (9.5 g, 67.3 mmol) in place of 3,4-difluoronitrobenzene. The reaction is run at 50 ° C overnight. Yield: 9.90 g (72%). MS (m / z): 221 [M + 1] +; Δ NMR (300 MHz, CDCl3): δ 8.15 (d, 2H), 6.83 (d, 2H), 3.80 (t, 4H), 2.61 (t, 4H).

Step 2: Preparation of 1- (4-nitrophenyl) -4- (triisopropylsilanyloxy) -1,2,3,6-tetrahydropyridine The title compound is prepared from 1- (4-nitrophenyl) piperidin- 4-one (Step 1.9, 90 g, 45 mmol) following the method described for EXAMPLE 69, Step 2, and purified by flash column chromatography &quot; 249 ΡΕ1478629 on silica gel (gradient 0 to 15% EtOAc in hexanes). Yield 9.70 g (57%). MS (m / z): 377 [M + 1] +; 1 H NMR (300 MHz, DMSO): δ 8.04 (d, 2H), 4.92 (d, 2H), 4.92 (t, 1H), 3.88 (bd, 2H) 66 (t, 2H), 2.50-2.20 (m, 2H), 1.97-1.12 (m, 3H), 1.02 (d, 18H).

Step 3: 1- (4-nitrophenyl) -2,3-dihydro-1H-pyridin-4-one The title compound is prepared from 1- (4-nitrophenyl) -4- (triisopropylsilanyloxy) 2,3,6-tetrahydropyridine (Step 2, 2.50 g, 6.65 mmol) following the method described for EXAMPLE 69, Step 3. The reaction is run for 4 h, and the product purified by column chromatography &quot; flash &quot; on silica gel (gradient from 5% to 60% EtOAc in hexanes). Yield 2.10 g (57%). MS (m / z): 219 [M + 1] +; 1 H NMR (300 MHz, CDCl 3): δ 8.39 (d, 2H), 7.49 (d, 1H), 7.14 (d, 2H), 5.39 (d, 1H), 4.06 (d, t, 4H), 2.72 (t, 4H).

Step 4: Preparation of 1- (4-aminophenyl) -2,3-dihydro-1H-pyridin-4-one The title compound is prepared from 1- (4-nitrophenyl) -2,3- pyridin-4-one (Step 3, 2.75 g, 12.6 mmol) following the method described for EXAMPLE 69, Step 4. Yield 2.0 g (84%). MS (m / z): 211 (M + Na) +.

Step 5: Preparation of (5R) -3- [4-2- (4-Oxo-3,4-dihydro-2A-pyridin-1-yl) phenyl] -2-oxo-5- To a stirred solution of 1- (4-aminophenyl) -2,3-dihydro-1H-pyridin-4-one (Step 4.550 mg, 2.90 mmol) in acetonitrile (5 mL) is added (2R) -2,3-epoxypropanate (563 mg, 4.90 mmol) and LiOTf (522 mg, 4.40 mmol). The resulting solution is stirred at 50-60 ° C for 22 h, at which time the reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography (5% acetone in CH 2 Cl 2) to afford the amino alcohol intermediate as an orange oil (275 mg, 31%, MS (m / z): 305.5 [M + H] +). The oil (258 mg, 0.85 mmol) is dissolved in acetonitrile (5 mL) followed by addition of CDI (309.5 mg, 1.91 mmol). The resulting reaction mixture is stirred at room temperature for 36 h, at which time the reaction is concentrated under reduced pressure to dryness. The residue is dissolved in EtOAc (50 mL) and washed with 50% aqueous citric acid solution (50 mL). The aqueous phase is washed with EtOAc (5 mL X 2), and the combined organic phase is dried over MgSO 4, filtered and concentrated under reduced pressure. The crude product is purified by silica gel chromatography (2% MeOH in CH2 Cl2) to give the title compound as a yellow solid (260 mg, 92%), MS (m / z) : 331.5 [M + H] +.

Step 6: Preparation of Ethyl 5 (R) -3- [4- (4-oxo-3,4-dihydro-25β, 14β, 14β (1 H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide Ethyl ester (5R) -2-Oxo-3- [4- (4-oxo-3,4-dihydro-2H-pyridin-1-yl) phenyl] oxazolidine-5-carboxylic acid (Step 5.213 mg, 0.64 mmol) is dissolved in 2.0M NH 3 in MeOH (8 mL) in a sealed glass vial. This mixture is heated at 60 ° C for 1.25 h, at which time the reaction is concentrated under reduced pressure and purified by silica gel column chromatography (using 2% MeOH in EtOAc and 2% MeOH (85 mg, 44%), 1 H NMR (300 MHz, DMSO) δ 7.85 (bs, 1H), 7.98 (s, , 7.30-7.55 (m, 3H), 7.30-7.26 (m, 2H), 5.03-4.97 (m, 2H), 4.27 (m, t, 1H), 4.01-3.93 (m, 3H); MS for C 15 H 15 N 3 O 4 m / z 302.5 (M + H) +. EXAMPLE 73 (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide

The title compound is prepared from (5R) -2-oxo-3- [4- (4-oxo-3,4-dihydro-2H-pyridin-1-yl) phenyl] oxazolidine-5-carboxylic acid (EXAMPLE 72, Step 5, 250 mg, 0.76 mmol) following the method described for EXAMPLE 70. Yield 130 mg (54%). MS for C 16 H 17 N 3 O 4 m / z 316.3 (M + H) +. EXAMPLE 74 (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide

The title compound is prepared from (5R) -2-oxo-3- [4- (4-oxo-3,4-dihydro-2H-pyridin-1-yl) phenyl] oxazolidine-5-carboxylic acid (EXAMPLE 72, Step 5, 50 mg, 0.15 mmol) following the method described for EXAMPLE 71. Yield 27 mg (55%). MS for C17 H19 N3 O4 m / z 330.5 (M + H) +. EXAMPLE 75 (5R) -N- (2-Fluoroethyl) -3- [4- (4-oxo-3,4-dihydro-1 (2 H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide

To a stirred solution of (5R) -3- [4- (4-oxo-3,4-dihydro-2H-pyridin-1-yl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 72, Step 5, 226 mg, 0.68 mmol) in MeOH (2 mL) is added triethylamine (0.48 mL, 5.0 equiv). Then 2-fluoroethylamine hydrochloride (136 mg, 2.0 equiv) is added to the solution. The reaction mixture is heated at 50-60 ° C for 5 h, followed by stirring overnight at ambient temperature. The solvent is removed and the residue is dissolved in 20% MeOH / CH2 Cl2 in MeOH and purified by column chromatography (10% MeOH / CH2 Cl2). The title compound is obtained as a yellow solid (100 mg, 42%), 1 H NMR (300 MHz, DMSO, δ 8.69 (t, 1H), 7.75-7.27 (m, 5H (D, 1H), 4.55 (t, 1H), 4.39 (t, 1H), 4.29 (t, 1H), 5.09 (dd, 1H).

4.02-3.93 (m, 3H), 3.51-3.37 (m, 2H), 2.50-2.45 (m, 2H); MS for C 17 H 18 FN 304 m / z 348.5 (M + H) +. EXAMPLE 76 (5R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 1- (2,6-difluoro-4-nitrophenyl) piperidin-4-one The title compound is prepared following the method described for EXAMPLE 69, Step 1 using 3,4,5- trifluoromitrobenzene (3.00 g, 16.94 mmol). Yield 1.71 g, (40%). MS (m / z): 257 [M + 1] +; ¹ NMR (300 MHz, CDCl 3): δ 7.80 (d, 1H), 3.63 (dd, 4H), 2.59 (dd, 4H).

Step 2: Preparation of 1- (2,6-difluoro-4-nitrophenyl) -4- (triisopropylsilanyloxy) -1,2,3,6-tetrahydro-pyridine The title compound is prepared from 1- ( 2,6-difluoro-4-nitrophenyl) piperidin-4-one (Step 1, 1.73 g, 6.75 mmol) following the method described for EXAMPLE 69, 254 ΡΕ1478629

Step 2, and purified by flash chromatography &quot; on silica gel (0 to 25% EtOAc in hexanes). Yield

2.78 g (quant). 1 H NMR (300 MHz, CDCl 3): δ 7.73 (d, 2H, 4.89-4.86 (m, 1H), 3.90-3.87 (m, 2H), 3.50-3.45 (m, 2H), 2.34-2.30 (m, 2H), 1.07-0.99 (m, 21H).

Step 3: Preparation of 1- (2,6-difluoro-4-nitro-phenyl) -2,3-dihydro-1H-pyridin-4-one The title compound is prepared from 1- (2,6- 6-difluoro-4-nitrophenyl) -4- (triisopropylsilanyloxy) -1,2,3,6-tetrahydropyridine (Step 2, 3.10 g, 7.51 mmol) following the method described in EXAMPLE 69, Step 3 , in 30 min and purified by flash chromatography &quot; on silica gel (eluent: 50% EtOAc in hexanes). Yield 1.34 g (70%). MS (m / z): 255 [M + 1] +; 1 H NMR (300 MHz, CDCl 3): δ 8.23 (d, 2H), 7.53-7.49 (m, 1H), 5.23 (d, 1H), 3.95 (t, 2H), 2.53-2.47 (m, 2H).

Step 4: Preparation of 1- (4-amino-2,6-fluorophenyl) -2,3-dihydro-1H-pyridin-4-one The title compound is prepared from 1- (2,6- difluoro-4-nitrophenyl) -2,3-dihydro-1H-pyridin-4-one (Step 3, 1.34 g, 5.27 mmol) following the method described for EXAMPLE 69, Step 4. Yield 1.08 g (91%).

Step 5: Preparation of (5R) -3,25-Bistrifluoro-4- (4-oxo-3,4-dihydro-2'-pyridin-1-yl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid To a stirred solution of 1- (4-amino-2,6-fluoro-phenyl) -2,3-dihydro-1H-pyridin-4-one (Step 4, 553 mg , 2.46 mmol) in acetonitrile (20 mL) is added butyl (R) -glycidate (532 mg, 3.69 mmol) followed by LiOTf (770 mg, 4.93 mmol). The resulting solution is stirred at 50 ° C for 16 h at which time the reaction is quenched by the addition of water (20 mL) and extracted with EtOAc (20 mL X 3). The combined organic phase is dried over Na 2 SO 4, filtered and concentrated under reduced pressure to afford crude product which is passed through a short silica gel column (EtOAc) to give the aminoalcohol intermediate (620 mg, MS (m / z): 369.4 [M + H] +) which is used without further purification. To a stirred solution of this intermediate in acetonitrile (20 mL) is added CDI (750 mg, 4.62 mmol). The resulting solution is stirred at room temperature for 16 h, at which time the reaction is quenched by addition of water (20 mL) and diluted with EtOAc (25 mL). The organic phase is separated, followed by extraction of the aqueous phase with EtOAc (20 mL X 2). The combined organic phase is washed with water (20 mL) and brine (20 mL), dried over Na2 SO4 and concentrated under reduced pressure and the residue is purified by silica gel chromatography (EtOAc 50% in hexane to EtOAc) to give the title compound (219 mg, 24% over 2 steps), MS (m / z): 395.6 [M + H] +. 256 ΡΕ1478629

Step 6: Preparation of (5R) -3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidine- carboxamide (5R) -3- [3,5-Difluoro-4- (4-oxo-3,4-dihydro-2 H -pyridin-1-yl) phenyl] -2-oxo- 5-oxazo-lidinecarboxylic acid (Step 5, 200 mg, 0.50 mmol) is dissolved in a 2M solution of NH 3 in MeOH (4 mL, 8 mmol). The resulting solution is stirred at room temperature for 3 h, at which time the reaction mixture is concentrated under reduced pressure. The residue is washed with ether to give the title compound as an off-white solid (139 mg, 82%), δ NMR (300 MHz, DMSO) δ 7.89 (bs, 1H) , 7.54-7.38 (m, 3H), 5.07-4.98 (m, 2H), 4.26 (t, 1H), 4.01 (dd, 1H ), 3.78 (t, 2H); MS for C 15 H 13 F 2 N 3 O 4 m / z 338.4 (M + H) +. EXAMPLE 77 (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarb -amide

To a stirred solution of (5R) -3- [3,5-difluoro-4- (4-oxo-3,4-dihydro-2'-pyridin-1-yl) phenyl] - 2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 76, Step 5, 133 mg) in MeOH (1 mL) is added MeNH 2 (2 mL, 4.0 257 Å AND 147.729 mmol, 2.0 M solution in MeOH). The reaction mixture is then heated to 40-50 ° C until all the solid disappears. The solvent is removed and the residue is dissolved in 20% MeOH / CH 2 Cl 2 and purified by silica gel chromatography (10% MeOH / CH 2 Cl 2) to give the title compound as a yellow solid ( 100 mg, 765), δ NMR (300 MHz, DMSO) δ 8.40 (m, 1H), 7.52-7.38 (m, 3H), 5.08 (dd, 1H), 5.00 (d 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H), 2.65 (d, 3H), MS for C16 H15 F2 N3 O4 m / z 352.5 ( M + H) + Example 78 (5R) -N-Ethyl-3- [4- (4- (3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide

The title compound is prepared from (5R) -3- [3,5-difluoro-4- (4-oxo-3,4-dihydro-2 H -pyridin-1-yl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 76, Step 5, 60 mg) following the method described for EXAMPLE 71. NMR (300 MHz, DMSO): δ 8.48 (t, 1H), (M, 3H), 5.06 (dd, 1H), 4.99 (d, 1H), 4.26 (t, 1H), 4.01 (dd, 1H). , 79 (t, 2H), 3.20-3.10 (m, 2H), 1.04 (t, 3H); (5R) -3- [4- [3,4-Dihydro-4- (hydroxyimino) -1 (2H) -258-PY1478629 pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide

To a stirred solution of 5 (R) -3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide (EXAMPLE 69, 110 mg, 0.34 mmol) in pyridine (2 mL) is added hydroxylamine hydrochloride (95 mg, 1.38 mmol). To this mixture is added MeOH (1 mL) and CH 2 Cl 2 (1 mL) and the solution becomes clear. This solution is stirred for 16 h, at which time it is concentrated under reduced pressure. The residue is purified by silica gel chromatography (5% MeOH in EtOAc) to give the title compound as a white solid (18 mg, 16%) as a mixture of isomers E and Z, 1H NMR (300 MHz, DMSO) δ 10.32 (s, 1H, less abundant isomer), 10.06 (s, 1H, more abundant isomer), 7.61-7.53 (m, 2H), 7.35-7.7.20 (m, 2H), 6.76-6.64 (m, 1H), 5.59 (d, 1H, more abundant isomer), 5.19 (d, 1H, isomer), 5.04-4.99 (m, 1H), 4.25 (t, 1H), 4.02-3.96 (m, 1H), 3.65-3.50 (m, 2H), 2.71-2.66 (m, 2H); MS (ESI +) for C 15 H 15 FN 4 O 4 m / z 335 (M + H) +. EXAMPLE 80 (5R) -3- (2,2-Difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl) -2-oxo- oxazolidinecarboxamide

259 ΡΕ1478629

Step 1: Preparation of 2,2-difluoro-4-methyl-7-nitro-4 H -1,4-benzoxazin-3-one To a stirred suspension of 2,2-difluoro-7-nitro-AH-1,4-benzoxazin -3-one (WO 99/40094, 2.16 g, 9.38 mmol) in DMF (10 mL) is added K 2 CO 3 (1.94 g, 14.07 mmol) followed by addition of Mel (0.87 mL , 14.07 mmol). The resulting solution is stirred overnight at room temperature. To this reaction mixture is added water (50 mL), and the resulting solution is extracted with EtOAc (50 mL X 3). The combined organic phases are washed with water (50 mL) and brine (50 mL), dried over Na2 SO4 and concentrated under reduced pressure to give the title compound which is purified by passage through a gel column of (1.3 g, 57%), NMR (300 MHz, DMSO) δ 8.25-8.17 (m, 2H), 7.62 (d, 1H), 3.47 (s, , 3H).

Step 2: Preparation of 2,2-difluoro-4-methyl-7-amino-4H-1,4-benzoxazin-3-one To a stirred suspension of 2,2-difluoro-4-methyl-7-nitro-4H-1 (2.85 g, 53.32 mmol) in EtOH (20 mL) and water (10 mL) was added ammonium chloride (2.85 g, 53.32 mmol) . To this mixture is added iron (892 mg, 15.09 mmol) in 3 equal portions. The resulting mixture is heated to 80 ° C for 2 h, at which time the reaction is cooled to room temperature followed by addition of CH2 Cl2 (50 mL). The resulting mixture is 260 Âμl / 147.7929 filtered through celite and the filtrate is further diluted with water (50 mL). The organic layer is separated, followed by further extraction of the aqueous phase with CH2 Cl2 (50 mL X3). The combined organic phase is dried over Na2 SO4 and concentrated under reduced pressure, and the residue is purified by passing through a short silica gel column with EtOAc to give the title compound (1.05 g, qu. , MS (m / z): 215.5 [M + H] +.

Step 3: Preparation of (5R) -3- (2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl ) To a stirred solution of 2,2-difluoro-7-amino-4-methyl-4 H -1,4-benzoxazin-3-one (Step 2, 1.05 g, 90 mmol) in acetonitrile (25 mL) is added LiOF (841 mg, 5.39 mmol) followed by methyl (R) -glycidate (549 mg, 5.39 mmol). The resulting mixture is heated to 50 ° C overnight at which time HPLC indicates complete consumption of the starting material. The reaction is quenched by addition of water (50 mL), EtOAc (100 mL) and brine (50 mL). The organic phase is separated, followed by further extraction of the aqueous phase with EtOAc (20 mL X 3). The combined organic phase is dried over Na 2 SO 4, filtered and concentrated under reduced pressure, and the residue is passed through a short silica gel column (EtOAc) to remove the polar impurities of the aminoalcohol intermediate (MS (m / z) : 317.5 [M + H] +) This intermediate is dissolved in anhydrous acetonitrile (20 mL) followed by addition of CDI (1.58 g, 9.80 mmol, 2 eq, wrt of the above aniline) at temperature environment. The resulting reaction mixture is stirred overnight, at which time it is diluted with 0.1N HCl (10 mL). The resulting pale yellow precipitate is collected by filtration, washed with additional 0.1N HCl (25 mL) and water (100 mL) and dried under high vacuum to give the title compound (1.30 g, 77% for the two steps), MS (m / z): 342.7 [M + H] +.

Step 4: Preparation of (5R) -3- (2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo -5-oxazolidinecarboxamide To a stirred solution of (5R) -3- (2,2-difluoro-4-methyl-3-oxo-3,4-dihydro-2H- 4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxylic acid (Step 3, 50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M NH 3 in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h at which time the reaction is concentrated under reduced pressure and purified by silica gel chromatography (EtOAc) to give the title compound as a yellow- NMR (300 MHz, DMSO) δ 7.86 (bs, 1H), 7.61 (d, 2H), 7.52-7.41 (m, 2H), NMR (CDCl 3): δ (CDCl 3): δ (CDCl 3) ) + EXAMPLE 81 (5R) -N-Methyl-3- (2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7- yl) -2-oxo-5-oxazolidine-carboxamide

To a stirred solution of (5R) -3- (2,2-difluoro-4-methyl-3-oxo-3,4-dihydro-2 H -1,4-benzoxazin- 7-yl) -2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 80, Step 3, 50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M MeNH 2 in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h at which time a precipitate forms. The mixture is heated to become transparent, and the product is allowed to crystallize at ambient temperature as white needles. The crystals are separated, washed with ether and dried under high vacuum at 50øC to give the title compound (25 mg, 50%), 1 H NMR (300 MHz, DMSO) δ 8.38 (d, 1H) (Dd, 1H), 4.29 (t, 1H), 4.03 (dd, 1H), 7.60 (d, 1H), 7.51-7.41 (m, 2H) (5R) -3- (8-Fluoro-1-methanesulfonyl-phenyl) -methyl- methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide

hs

Step 1:

Preparation of 8-fluoro-3,4-dihydro-1-quinolin-2-one [prepared as described above] (2.62 g, 0.0159 mol) is dissolved in concentrated sulfuric acid (20 ml) and cooled to -5 ° C. Nitric acid (70%, 1.02 mL, 0.0159 mol) is added dropwise and the reaction stirred at -5 ° C for 20 minutes. The mixture is poured onto ice and the resulting precipitate collected by filtration, well washed with water, and dried under vacuum. Purification by flash column chromatography &quot; (30% ethyl acetate / hexane) gives the title compound as a pale yellow solid (2.50 g, 75%); [M + H] + = 211.

Step 2: Preparation of 8-fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one quinolin-2-one (Step 1, 3.13 g, 0.0149 mol) and iodomethane (1.39 ml, 0.0223 mol) in DMF (25 ml) are stirred at room temperature overnight. The reaction is diluted with water and the resulting precipitate collected by filtration, well washed with water, and dried under vacuum to give the title compound as an orange solid (2.97 g, 89%); Δ NMR (300 MHz, CDCl3) δ 2.56-2.61 (m, 2H), 2.99-3.04 (m, 2H), 3.32 (s, 3H), overlapping 8.06 (m, s, 1H) and 8.08 (dd, 1H); [M + H] + = 225. 264 ΡΕ1478629

Step 3: Preparation of 6-amino-8-fluoro-1-methyl-3,4-dihydro-1 H -quinolin-2-one 8-Fluoro-1-methyl-6-nitro-3,4- dihydro-1H-quinolin-2-one (Step 2, 2.28 g, 0.0102 mol) is heated in ethanol (75 ml) until dissolved. Water (25 ml) and ammonium chloride (5.46 g, 0.102 mol) are added and the mixture is heated to 90øC. Iron powder (2.27 g, 0.0407 mol) is added in portions and the mixture is stirred and heated for 30 minutes. The reaction is cooled and dichloromethane (200 ml) is added. The mixture is filtered and the separated organic layer, washed with brine, dried (MgSO4) and evaporated to give the title compound as a yellow solid (1.98 g, 99%); [M + H] + = 195.

Step 4: Preparation of 3- (8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino) -2-hydroxypropionic acid methyl ester 6-Amino -8-fluoro-1-methyl-1,3,4-dihydro-1-quinolin-2-one (Step 3, 2.25 g, 0.0116 mol), methyl (2R) -glycidate ( 1.18 g, 0.0116 mol) and lithium trifluoromethanesulfonate (1.81 g, 0.0116 mol) in acetonitrile (10 ml) are heated at 90 ° C overnight. The reaction is concentrated and the residue diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography &quot; (50% ethyl acetate / hexane) to give the title compound as a yellow solid (2.13 g, 62%); MS (m / z): [M + H] + = 297.

Step 5: Preparation of (5R) -3- (8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2- 5-oxazolidinecarboxylic acid

Phosgene (20% solution in toluene, 4.07 ml, 7.69 mmol) is added dropwise at 0 ° C to 3- (8-fluoro-1-methyl-2-oxo-1 (Step 4, 1.81 g, 6.41 mmol) and triethylamine (2.23 mL, 16.0 mmol) in dichloromethane (25 ml). The mixture is allowed to warm to room temperature and stirred for an additional hour. The reaction is washed with 2N aqueous hydrochloric acid and brine, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography &quot; (50% ethyl acetate / hexane) to give the title compound as a white solid (1.71 g, 83%); MS (m / z): [M + H] + = 323.

Step 6: Preparation of (5R) -3- (8-fluoro-1-methyl-2-fluoro-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide

3- (8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidine carboxylic acid methyl ester (Step 5, 0.300 g, 9.31 mmol) is dissolved in 2M ammonia solution in methanol (8 ml) and stirred overnight at room temperature. The resulting precipitate 266 ΡΕ1478629 is filtered, washed with methanol, and dried under vacuum to give the title compound as a white solid (0.185 g, 65%), mp 260-2øC; 1 H NMR (300 MHz, CDCl 3) δ 2.48-2.52 (m, 2H), 2.85-2.89 (m, 2H), 3.28 (d, 3H), 4.00 (dd, 1H), 7.24 (s, 1H), 7.46 (dd, 1H), 7.62 (bs, 1H), 7.64 , 87 (br s, 1H); MS for C 14 H 14 FN 3 O 4 m / z 308 (M + H) +. EXAMPLE 83 (5R) -N-Methyl-3- (8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide

3- (8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidine carboxylic acid methyl ester (EXAMPLE 82, Step 5, 0.300 g, 9.31 mmol) is dissolved in 2M methylamine solution in methanol (8 ml) and stirred overnight at room temperature. The resulting precipitate is filtered, washed with methanol, and dried under vacuum to give the title compound as a white solid (0.145 g, 48%), mp 264-5øC; 1 H NMR (300 MHz, CDCl 3) δ 2.47-2.52 (m, 2H), 2.64 (d, 3H), 2.84-2.89 (m, 2H), 3.27 (d, 3H), 4.00 (dd, 1H), 4.24 (t, 1H), 5.06 (dd, 1H), 7.26 (s, 1H), 7.46 (dd, 1H) 39 (d, 1H); MS for C 15 H 16 FN 304 m / z 322 (M + H) +. EXAMPLE 84 3- (4-Methyl-3-thioxo-3,4-dihydro-2 H -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide 267 ΡΕ1478629

Step 1: Preparation of (5R) -3- (3,4-dihydro-4-methyl-3-thioxo-2H-1,4-benzothiazin-7-yl) -2- 5-oxazolidinecarboxylic acid methyl ester To a stirred suspension of (5R) -3- (3,4-dihydro-4-methyl-3-oxo-2 H -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 62, Step 5, 1.26 g, 3.907 mmol) in dry dioxane (25 mL) is added Lawesson's Reagent (2.37 g, 5.861 mmol). This reaction mixture is heated at 70-80 ° C for 1.5-2 h at which time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is washed with EtOAc (15 mL X 3), sonicated and filtered to give the title compound as a yellow solid (1.18 g, 89%), MS (m / z): 339.5 [M + H] +.

Step 2: Preparation of 3- (4-methyl-3-thioxo-3,4-dihydro-2 H -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide To a stirred suspension (5R) -3- (3,4-dihydro-4-methyl-3-thioxo-2 H -1,4-benzothiazin-7-yl) -2-oxo-5- (Step 1.100 mg, 0.2955 mmol) in MeOH (3 mL) is added 2.0 M ammonia in MeOH (1.0 mL). This mixture is heated at 40 ° C for 24 h at which time the reaction is concentrated under reduced pressure. The residue is washed with MeOH (4 mL) and purified by column chromatography (2% MeOH / CH 2 Cl 2) to give the title compound as a white solid (25 mg, 26%), NMR (300 MHz, DMSO) δ 7.87 (bs, 1H), 7.64 (d, 2H), 7.51 (s, 2H), 5.03 (dd, 1H), 4.28 (t, 1H), 4.02 (dd, 1H), 3.85 (s, 2H), 3.32 (s, 3H); MS for C 13 H 13 N 3 O 3 S 2 m / z 324.5 (M + H) +. EXAMPLE 85 (5R) -N-Methyl-3- [3-fluoro-4- (trans -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 42, and making non-basic variations, but substituting butyl (5R) -3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylate (5R) -3- [3-fluoro-4- (trans-tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidine carboxylate (EXAMPLE 24, Step 1) and purifying the residue by chromatography on a Biotage Flash 40S cartridge of 40 g of silica gel, eluting with the MeOH / CH 2 Cl 2 gradient (2 / 98-4 / 96), the title compound is obtained

The II &lt; J-1020 by TLC (MeOH / CHCl3, 10/90)], NMR (400MH [Z, DMSO-d6) δ8. (Dd, 1H), 7.33 (m, 2H), 5.06 (dd, 1H), 4.27 (t, 1H), 4.00 (dd, 1H ), 3.38 (m, 2H), 3.06 (m, 1H), 2.81 (m, 2H), 1.99 (m, 2H), 1.88 (m, 2H), MS: 269 ΡΕ1478629 (ΙΕΡ +) for C 16 H 19 N 2 O 4 FS m / z 355 (M + H) +. EXAMPLE 86 (5R) -3- (4-Fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 2- (benzyloxy) -6-fluorobenzamide Benzyl alcohol (24 ml, 0.229 mol) is added portionwise to a suspension of sodium hydride (9.16 g, 0.229 mol) in DMF (300 ml) and stirred at room temperature for 1 h. 2,6-Difluorobenzamide (30 g, 0.190 mol) is added in one portion and stirring is continued overnight at room temperature. The reaction mixture is poured into 1N HCl (1.5 L) and extracted with dichloromethane. The extract is washed with water and brine, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (39.6 g, 85%); MS for C 14 H 12 FNO 2 m / z 246 (M + H) +.

Step 2: Preparation of 2- (benzyloxy) -6-fluoroaniline

Sodium hypochlorite (10% aqueous solution, 69.1 ml, 0.112 mol) is added at 0 ° C portionwise to a mixture of 2- (benzyloxy) -6-fluorobenzamide (Step 1, 22.89 g, 0933 mol) and sodium hydroxide (9.33 g, 0.233 mol) dissolved in water (200 ml) and dioxane (200 ml). The mixture is heated at 70 ° C for 1 h, cooled to room temperature, and then extracted with ether. The ether extract is washed with water and brine, dried (MgSO4), and evaporated to give a pale brown oil. Purification by flash column chromatography &quot; (10% ethyl acetate / hexane) gives pure product as a colorless oil (18.2 g, 90%).

Step 3: Preparation of 2-amino-3-fluorophenol 2- (Benzyloxy) -6-fluoroaniline (Step 2, 5.00 g, 0.0230 mol) and 10% palladium on carbon (0.5 g) in methanol (100 ml) are stirred under a hydrogen atmosphere (flask) for 2 h. The catalyst is removed by filtration through a pad of celite and the filtrate concentrated to give pure product as a tan solid (2.9 g, 99%); mp 125-6 ° C.

Step 4: Preparation of 4-fluoro-1,3-benzoxazol-2 (3H) -one 1,1'-Carbonyl diimidazole (11.4 g, 0.0703 mol) is added in portions to a solution of 2-amino- 3-fluoro-phenol (Step 3, 8.94 g, 0.0703 mol) in THF (200 mL) and heated at 60 ° C for 2 h. The reaction mixture is diluted with ethyl acetate (200 mL), washed with 2N HCl and brine, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10 , 6 g, 99%); mp 131-3 ° C. 271 ΡΕ1478629

Step 5: Preparation of 4-fluoro-6-nitro-1,3-benzoxazol-2 (3H) -one Nitric acid (70%, 2.50 mL, 0.0389 mol) is added dropwise at -10 To a solution of 4-fluoro-1,3-benzoxazol-2 (3H) -one (Step 4, 5.95 g, 0.0389 mol) in concentrated sulfuric acid (60 mL). The reaction is stirred at -10 ° C for 30 minutes and then poured into ice-water. The resulting precipitate is collected by filtration and dried under reduced pressure to give the desired product contaminated with approximately 10-15% of the undesired 5-nitro isomer (7.2 g, 93%); mp 177-9 ° C.

Step 6: Preparation of 4-fluoro-3-methyl-6-nitro-1,3-benzoxazol-2 (3H) -one

Iodomethane (0.393 ml, 6.31 mmol) is added in portions to crude 4-fluoro-6-nitro-1,3-benzoxazol-2 (3H) -one (Step 5, 1.00 g, 5.05 mmol) and 1,8-diazabicyclo [5.4.0] un-dec-7-ene (0.94 mL, 6.31 mmol) in DMF (10 mL). The reaction is stirred at 65 ° C overnight, diluted with ethyl acetate, washed with 2N HCl and brine, dried (MgSO 4), and evaporated to give crude product containing trace amounts of the 5-nitro isomer Not Desired. Purification by flash column chromatography &quot; (20% ethyl acetate / hexane) gives pure product as a white solid (0.89 g, 83%); mp 118-9 ° C.

Step 7: Preparation of 6-Amino-4-fluoro-3-methyl-1,3-benzo-2,7-dihydro-2 (3H) -one Iron powder (0.77 g, 0.0138 mol) is added in To a mixture of 4-fluoro-3-methyl-6-nitro-1,3-benzoxazol-2 (3H) -one (Step 6, 0.73 g, 3.44 mmol) and ammonium chloride g, 3.44 mmol) in ethanol (30 mL) and water (15 mL) at 95 ° C. The reaction mixture is stirred vigorously and heated for 1 h, cooled to room temperature, and diluted with dichloromethane (150 ml). The mixture is filtered, washed with water and brine, dried (MgSO4) and evaporated to give product as a tan solid suitable for use in the next step (0.64 g, 99%).

Step 8: Preparation of methyl (2R) -3 - [(4-fluoro-3-methyl-2-hydroxymethyl-2,3-dihydro-6-benzoxazolyl) amino] -2-hydroxypropanoate

A mixture of 6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2 (3H) -one (Step 7, 0.630 g, 3.46 mmol), methyl (2R) -glycidate (0.353 g , 3.46 mmol) and lithium trifluoromethanesulfonate (0.540 g, 3.46 mmol) in acetonitrile (10 mL) is stirred and heated at 90 ° C overnight. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated under reduced pressure. Final purification by flash column chromatography &quot; (50% ethyl acetate / hexane) gives pure product as a white solid (0.98 g, 60%); MS for C 12 H 13 FN 2 O 5 m / z 285 (M + H) +. 273 ΡΕ1478629

Step 9: Preparation of methyl (5R) -3- (4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate

A mixture of methyl (2R) -3 - [(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl) amino] -2-hydroxypropanoate (Step 8, 0.84 g, 2.96 mmol), 1,1-carbonyldiimidazole (0.48 g, 2.96 mmol) in acetonitrile is stirred and heated at 60 ° C overnight. The reaction is diluted with ethyl acetate, washed with 2N HCl and brine, and evaporated under reduced pressure. The resulting solid is triturated with methanol to give pure product as a white solid (0.88 g, 96%); MS for C 13 HU FN 2 O 6 m / z 311 (M + H) +.

Step 10: Preparation of (5R) -3- (4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

A solution of ammonia in methanol (2M, 5 mL) is

was added to solid methyl (5R) -3- (4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-1,3-oxazolidine-5-carboxylate (Step 9, 0.250 g, 0.806 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue purified by means of pCCF (10% methanol / dichloromethane) to give product as a white solid (0.13 g, 55%); MS for C 12 H 10 FN 3 O 5 m / z 296 (M + H) +; 1 H NMR (DMSO-d 6, 300 MHz) δ 7.87 (bs, 1H), 7.63 (bs, 1H), 7.50 (d, 1H) , 5.03 (dd, 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.42 (s, 3H). EXAMPLE 87 (5R) -3- (3-Ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 3-ethyl-4-fluoro-6-nitro-1,3-benzoxazol-2 (3H) -one

Prepared from iodoethane (0.61 ml, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2 (3H) -one (EXAMPLE 86, Step 5, 1.2 g, 6 (1.13 mL, 7.57 mmol) in DMF (10 mL) according to the method of EXAMPLE 86, Step 6 (1.10 g, 80%); mp 121-2 ° C.

Step 2: Preparation of 6-amino-3-ethyl-4-fluoro-1,3-benzoxazol-2 (3H) -one

Prepared from 3-ethyl-4-fluoro-6-nitro-1,3-benzoxazol-2 (3H) -one (Step 1, 1.05 g, 4.90 mmol), ammonium chloride (2.62 (1.09 g, 19.6 mmol) in ethanol (30 mL) and water (15 mL) according to the method of EXAMPLE 86, Step 7 (0.95 g, 99 mmol) %).

Step 3: Preparation of methyl (2R) -3 - [(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl) amino] -2-hydroxypropanoate

Prepared from 6-amino-3-ethyl-4-fluoro-1,3-benzoxazol-2 (3H) -one (Step 2, 0.90 g, 4.59 mmol), methyl (2R) -glycidate (0.46 g, 4.59 mmol) and lithium trifluoromethanesulfonate (0.716 g, 4.59 mmol) in acetonitrile (10 mL) according to the method of EXAMPLE 86, Step 8 (1.11 g, 81 mmol) %); MS for C 13 H 15 FN 2 O 5 m / z 299 (M + H) +.

Step 4: Preparation of methyl (5R) -3- (3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate

Prepared from methyl (2R) -3 - [(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl) amino] -2-hydroxypropanoate (Step 3, (0.549 g, 3.39 mmol) according to the method of EXAMPLE 86, Step 9 (1.10 g, 99%); 1H NMR (DMSO-d6):? MS for C 14 H 13 FN 2 O 6 m / z 325 (M + H) +.

Step 5: Preparation of (5R) -3- (3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Prepared from methyl (5R) -3- (3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate (Step 4 , 0.250 g, 0.771 mmol) and methanol in methanol (5 mL) according to the method of EXAMPLE 86, Step 10 (0.15 g, 63%); MS for C 13 H 12 FN 3 O 5 m / z 310 276 ΡΕ1478629 (Μ + Η) +; NMR (DMSO-d6, 7.52 (d, 1H), 4.02 (dd, 1H), 3.0 (m, 1H), 7.44 (dd, 3.86 (s, 1H), 7.63 (s, 1H), 5.03 (dd, 1H), 4.26 (s, 1H), 1.28 (t, 3H) ) -3- (4-Fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 4-fluoro-3-isopropyl-6-nitro-1,3-benzoxazol-2 (3H) -one

Prepared from 2-iodopropane (0.76 mL, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2 (3H) -one (EXAMPLE 86, Step 5, 1.2 g (1.13 mL, 7.57 mmol) in DMF (10 mL) according to the method of EXAMPLE 86, Step 6 (0.87 g, 60%); mp 122-3 ° C.

Step 2: Preparation of 6-amino-4-fluoro-3-isopropyl-1,3-benzoxazol-2 (3H) -one

Prepared from 4-fluoro-3-isopropyl-6-nitro-1,3-benzoxazol-2 (3H) -one (Step 1, 0.87 g, 3.64 mmol), ammonium chloride (1.95 (0.81 g, 14.6 mmol) in ethanol (30 mL) and water (15 mL) according to the method of EXAMPLE 86, Step 7 (0.77 g, , 99%). 277 ΡΕ1478629

Step 3: Preparation of methyl (2R) -3 - [(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) amino] -2-hydroxypropanoate

Prepared from 6-amino-4-fluoro-3-isopropyl-1,3-benzoxazol-2 (3H) -one (Step 2, 0.77 g, 3.66 mmol), (2R) -glycidate (0.57 g, 3.66 mmol) in acetonitrile (10 mL) according to the method of EXAMPLE 86, Step 8 (0.37 g, 3.66 mmol) and trifluoro-methanesulfonate 89 g, 78%); MS for C 24 H 28 F 4 N 3 O 3: m / z 313 (M + H) +.

Step 4: Preparation of methyl (5R) -3- (4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate

Prepared from methyl (2R) -3 - [(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) amino] -2-hydroxypropanoate (Step 3, 0.891 g, 2.91 mmol) and 1,1'-carbonyldiimidazole (0.471 g, 2.91 mmol) according to the method of EXAMPLE 86, Step 9 (0.90 g, 92%); MS for C 15 H 15 FN 2 O 6 m / z 339 (M + H) +.

Step 5: Preparation of (5R) -3- (4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide

Prepared from methyl (5R) -3- (4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxylate ( Step 4, 0.250 g, 7.39 mmol) and ammonia in methanol (5 mL) according to the method of Example 86, Step 10 (0.14 g, 59%); MS for C 14 H 14 FN 3 O 5 m / z 324 (M + H) +; Δ NMR (DMSO-d 6, 300 MHz, δ 7.88 (bs, 1H), 7.63 (bs, 1H), 7.53 (d, 1H), 7.44 (dd, 1H), 4.06 (dd, 1H), 1.41 (dd, 6H), 4.05 (dd, 1H), 4.55 (m, 1H) 3- (4-Fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -N-methyl-2-oxo-5-oxazolidinecarboxamide

A solution of methylamine in methanol (2M, 5 mL) is added to (5R) -3- (4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo -5-oxazolidinecarboxylate (EXAMPLE 86, Step 9, 0.250 g, 0.806 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified via pCCF (10% methanol / dichloromethane) to give product as a white solid (0.049 g, 19%); MS for C 13 H 12 FN 3 O 5 m / z 310 (M + H) +; NMR (DMSO-d6, 300 MHz) δ 8.40 (m, 1H), 7.49 (d, 1H), 7.42 (dd, 1H), 5.07 (dd, 1H), 4.26 (5R) -3- (3-Ethyl-4-fluoro-2-methoxyphenyl) -1H-indol- 2-oxo-2,3-dihydro-6-benzoxazolyl) -N-methyl-2-oxo-5-oxazolidinecarboxamide 279 ΡΕ1478629 - &quot;

A solution of methylamine in methanol (2M, 5 mL) is added to (5R) -3- (3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo -5-oxazolidinecarboxylate (EXAMPLE 87, Step 4, 0.250 g, 0.771 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified by pCCF (10% methanol / dichloromethane) to give product as a white solid (0.10 g, 40%); MS for C 14 H 14 FN 3 O 5 (m / z) 324 (M + H) +; Δ NMR (DMSO-d 6, 300 Mhz) δ 8.40 (m, 1H), 7.51 (d, 1H), 7.44 (dd, 1H), 5.07 (dd, 1H), 4.27 1H), 4.02 (dd, 1H), 3.85 (q, 2H), 2.65 (d, 3H), 1.28 (t, 3H) EXAMPLE 91 (5R) -3- ( 4-Fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -N-methyl-2-oxo-5-oxazolidinecarboxamide

A solution of methylamine in methanol (2M, 5 mL) is added to (5R) -3- (4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl) -2-oxo -5-oxazolidinecarboxylate (EXAMPLE 88, Step 4, 0.250 g, 0.739 mmol) and the suspension stirred overnight at ambient temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified via pCCF (10% methanol / dichloromethane) to give product as a white solid (0.05 g, 20%); MS for C 15 H 16 FN 3 O 5 m / z 338 (M + H) +; NMR (DMSO-d 6, 300 MHz) δ 8.40 (m, 1H) (d, 1H), 7.43 (dd, 1H), 5.08 (dd, 1H), 4.54 (m, 1H) (t, 1H), 4.03 (dd, 1H), 2.65 (d, 3H), 1.41 (dd, 6H).

EXAMPLE 92: ADDITIONAL COMPOUNDS

Other compounds of this invention may be synthesized by the methodology described herein. Further compounds of the invention include, but are not limited to, the following: 1. (5R) -3- (2-Formyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7- -2-oxo-5-oxazolidinecarboxamide 2. (5R) -N-Methyl-3- (2-formyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide 3. (5R) -3- [2- (Hydroxyacetyl) -2,3,4,5-tetrahydro-1-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide 4. (5R) -N- 3- [2- (hydroxyacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide 5. (5R) -3- (3-Formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) ethyl] -2-oxo-5-oxazolidinecarboxamide. (5R) -N-Methyl-3- (3-formyl-2,3,4,5-tetrahydro-3-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide 7. (5R) -3- [3- (Hydroxyacetyl) -2,3,4,5-tetrahydro-1 H -3-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide 8. (5R) -N- Methyl-3- [3- (hydroxyacetyl) -2,3,4,5-tetrahydro-3-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide 9. (5R) -N-Methyl-3- (3,5-Difluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide. (3,5-Difluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide 11. (5R) -3- [3-Fluoro-4- (5R) -N-Methyl-3- [3-fluoro-4- (1-formyl-3-methylazetidin-1-yl) -2-oxazolidinecarboxamide 3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide 13. (5R) -3- [4- (cis-1- (methylimino) -1-oxido-1,3,3,4,5,6-hexa dihydro-2 H -pyrazan-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide 14. (5R) -N-Methyl-3- [4- (cis-1-imino -1-oxido-1,1,3,4,5,6-hexahydro-2 H -pyrazan-4-yl) -3-fluorophenyl] -2-oxo-5-hydroxy-2-oxazolidinecarboxamide 15. ( 5R) -N-Methyl-3- [4- (cis-1- (methylimino) -1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2- (5R) -3- [4- (trans-1- (imino) -1-oxido-1,3,3,4,5,6-hexahydro-2 H -thiopyran- 4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide 17. (5R) -N-Methyl-3- [4- (trans-1- (imino) (5R) -3- [4-Amino-5-oxazolidinecarboxamide] -1,2,3,4,5,6-hexahydro-2 H -pyrazan-4-yl) -3-fluorophenyl] - (trans-1- (methylimino) -1-oxido-1,3,4,5,6-hexahydro-2 H -pyrazan-4-yl) -3-fluorophenyl] -2-oxo -5-oxazolidinecarboxamide 19. (5R) -N-Methyl-3- [4- (trans-1- (methylimino) -1-oxido-1,1,3,4,5,6-hexahydro- thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide 20. (5R) -3- [4- (1- (2 (S) -Hydroxy-3-phosphorylpropanoyl) -1,2,5,6- 4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide 21. (5R) -N-Methyl-3- [4- (1- (2 (S) -hydroxy-3- propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluoro-283α-androstane-2-oxo-5-oxazolidinecarboxamide 22. (5R) -3- [4- (1- (2 (S), 3-Dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide 23. ( 5R) -N-Methyl-3- [4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl] -2- oxo-5-oxazolidinecarboxamide 24. (5R) -3- [4- (1- (2 (S) -Hydroxy-3-phosphorylpropanoyl) -1,2,5. (5R) -N-Methyl-3- [4- (1- (2 (S) -hydroxy-3-oxo-5-oxazolidinecarboxamide] 4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide 26. (5R) -3- [4- (1- (2 (S) -Dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; and 27 (5R) -N-Methyl-3- [4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] 2-oxo-5-oxazolidinecarboxamide 28. (5R) -3- (3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2 H -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide ΡΕ1478629 29. (5R) -N-Methyl-3- (3,4-dihydro-5-fluoro-4-methyl-3-hydroxy-2H-1,4-benzothiazin-7-yl) -2-oxo -5-oxazolidinecarboxamide. (5R) -3- (3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2,3-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide (5R) -N-Methyl-3- (3,4-dihydro-5-fluoro-4-methyl-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo-5- (5R) -3- (2,3-Dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide 33. (5R) -N- 3-methyl-3- (2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide 34. (5R) -3- (2,3- 4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide 35. (5R) -N-Methyl-3- (2,3-dihydro- 3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide 36. (5R) -3- (2,3-Dihydro-3-isopropyl-4-fluoro-2- (5R) -N-Methyl-3- (2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-oxazolidinecarboxamide benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide 38. (5R) -3- [4- (3,6-Dihydro-2 H -thiopyran-4-yl) -5β, 14β, 14β, -difluorophenyl] -2-oxo-5-oxazolidinecarboxamide 39. (5R) -3- [4- (3,6- dihydro-2H-thiopyran-4-yl) -3,5-difluorophenyl] -N-methyl-2-oxo-5-oxazolidine-carboxamide 40. (5R) -3- [3-Fluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 41. (5R) -N- 4-Fluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 42. (5R) -3- [3- methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 43. (5R) -N-Methyl-3- [3-Fluoro-4- (1-methylimino- 4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 44. (5R) -3- [3,5-Difluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2 oxo-5-oxazolidinecarboxamide 45. (5R) -N-Methyl-3- [3,5-Difluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 46. (5R) -3- [3,5-Difluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 47. (5R) -N- Methyl-3- [3,5-Difluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide 286 ΡΕ1478629

Test Method for CIM

The in vitro MICs of the test compounds are determined by a standard agar dilution method. The stock drug solution of each analog is prepared in the preferred solvent, usually DMSO: H2 O (1: 3). Serial 2-fold dilutions of each sample are made using 1.0 ml aliquots if sterile distilled water. To each 1.0 ml aliquot of drug is added 9 ml of molten Mueller Hinton's medium. The drug-supplemented agar is mixed, poured into 15 x 100 mm petri dishes, and allowed to solidify and dry prior to inoculation.

Vessels from each of the test organisms are kept frozen in the vapor phase of a liquid nitrogen freezer. Test cultures are grown overnight at 35 ° C in the medium appropriate for the body. Colonies are harvested with a sterile wick, and cell suspensions are prepared in Tryticase Soy Broth (TSB) until the turbidity of a 0.5 McFarland standard is achieved. A 1:20 dilution of each suspension is made in TSB. Plates containing the drug-supplemented agar are inoculated with one drop of 0.001 ml of the cell suspension using a Steers replicator, yielding approximately 104 to 105 cells per spot. The plates are incubated overnight at 35 ° C. Following the incubation is read and recorded the Concen- 287 ΡΕ1478629 tensile traction nismo. Table

The data are shown in Table I. 1: MICs of Compounds of Formula I for Staphylococcus aureus (SAUR 9213), the lowest inhibitory concentration (CIM μg / ml), the lowest concentration of drug inhibiting visible organ growth

Example No. CIM æg / ml) 1 4 2 8 3 8 4 16 5 16 6 16 7 2 8 1 9 4 10 4 11 4 12 2 13 2 14 4 15 2 17 4 18 16 20 4 21 8 22 4 ΡΕ1478629 288 23 4 24 2 25 8 26 16 27 8 29 1 30 1 31 1 32 1 33 4 34 8 35 2 36 2 37 2 38 1 39 1 40 4 41 2 42 4 43 4 44 4 45 4 46 8 47 4 48 2 49 8 50 2 51 2 ΡΕ1478629 289 52 2 53 2 54 0.5 55 1 56 4 57 8 58 8 59 2 60 2 61 8 62 4 63 4 64 0.5 65 2-4 66 4 67 2 68 4 69 2 70 2 71 4 72 2 73 2 74 8 75 8 76 4 77 2 78 8 79 1 ΡΕ1478629 290 80 2 81 4 82 1 83 2 84 2 85 2 86 4 87 2 88 4 89 16 90 4 91 4

Lisbon November 23, 2006

Claims (26)

A compound of formula I or a pharmaceutically acceptable salt thereof wherein: A represents a structure i, ii, or iii C represents aryl or heteroaryl, wherein each of the aryl and heteroaryl are optionally substituted with 1-3 of R2; B is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, het and het substituted, or B and an R2, if present, together with the phenyl carbon atoms to which B and R 2 and R 2 are attached, form a het, wherein het is optionally substituted het, provided that when C represents phenyl optionally substituted with R 2 then B does not represent ΡΕ1478629 2 wherein Q is independently selected from H, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, phenyl, benzyl, -OH, CF 3, CCI 3, -NR 3 R 3, -C 1 -C 6 alkylene-NR 3 R 3, C 1 -C 6 alkylene - (CH 2 -phenyl) -NR 3 R 3, C 1 -C 6 alkylene- (CH 2 benzyl) -NR 3 R 3, and O R1 is selected from H, -OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino, substituted alkyl, substituted alkoxy, and substituted alkenyl; Each R 2 is independently selected from H, alkyl, amino, NO 2, -CN, halo, and substituted alkyl; and each R 3 is independently selected from H or C 1 -C 6 alkyl. A compound of claim 1 of formula II Or a pharmaceutically acceptable salt thereof wherein: A represents a structure i, ii, or iii π O OB is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, het, and het substituted, or B and a R2 together with the phenyl carbon atoms to which B and R2 are bonded, form a het, and het is optionally substituted het, provided B does not represent where Q is independently selected from H, C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, phenyl, benzyl, -OH, CF 3, CC 13, -NR 3 R 3, -C 1 -C 6 alkylene-NR 3 R 3, C 1 -C 6 alkylene - (CH2phenyl) -NR3R3, C1 -C6 alkylene- (CH2 benzyl) -NR3 R3, and O The 4 ???????? R14 is selected from H, -OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino, substituted alkyl, substituted alkoxy, and substituted alkenyl; Each R 2 is independently selected from H, alkyl, amino, NO 2, -CN, halo, and substituted alkyl; Each R 3 is independently selected from H or C 1 -C 6 alkyl. 3. The compound of claim 2, wherein v is The compound of claim 2, wherein R1 is H, -NH2, -OH, C1-4 alkyl, C3-5 cycloalkyl, C1-4 alkoxy, or C2-4 alkenyl, the alkyl, alkoxy and alkenyl being each one of them, optionally substituted with one or more halo, -OH, -CN. The compound of claim 4, wherein R 1 is H, -OH, -CH 2 -CH = CH 2, methyl, ethyl, propyl, -CH 2 -CH 2 -F, -CH 2 -CH 2 OH, or methoxy. The compound of claim 2 or 5, wherein B represents het or het substituted. The compound of claim 6, wherein B represents morpholinyl, piperazinyl, pyridyl, thiomorpholinyl, 3,6-dihydro-2 H -thiopyranyl, tetrahydro-2 H -thiopyranyl, 3,6- dihydro-2 H -pyranyl, tetrahydro-2 H -pyranyl, azetidinyl, 5,6-dihydro-4H- [1,3,4] thiadiazinyl, 2,5-dihydro-1 H -pyrrolyl, 3- , 4-dihydro-1 (277) -pyridinyl, tetrahydropyridyl, 5,7-dihydro-6,7-pyrrolo [3,4-b] pyridinyl, 2,3-dihydro-477-1,4- thiazinyl, each of which is morpholinyl, piperazinyl, pyridyl, thiomorpholinyl, 3,6-dihydro-2 H -thiopyranyl, tetrahydro-2 H -thiopyranyl, 3,6-dihydro-2 H -pyranyl, tetrahydro- 2-pyridyl, azetidinyl, 5,6-dihydro-4 H - [1,3,4] thiadiazinyl, 2,5-dihydro-1 H -pyrrolyl, 3,4-dihydro-1 (277) tetrahydropyridyl, 5,7-dihydro-6,7-pyrrolo [3,4-b] pyridinyl, 2,3-dihydro-4 H -1,4-thiazinyl optionally substituted with 1-4 groups selected from starting from = O, alkyl, substituted alkyl, amino, substituted amino, -OH, = NOH, = N-C1-4 alkyl, and halo. The compound of claim 7, wherein B is selected from ΡΕ1478629 6 The compound of claim 2, wherein one R2 is hydrogen and the other R2 is F. 7 ΡΕ1478629 The compound of claim 2, wherein both R2 represents F. The compound of claim 2, wherein R2 and B together form a het. The compound of claim 11, wherein R2 and B form -CO (O) -N (Q50) -OC (O) -N (Q50) -N (Qso) -HCQ5o-CH2-, -NOSso-C ( O) -CH 2 -O-, -NQ 50 -C (O) -CF 2 -O-, -NQ 50 -C (O) -CH 2 -S-, -NOSso-C (O) -CF 2 -S, -NOSso-C (S) -CH 2 -S-, -NQ 50 -C (O) -CH 2 -CH 2 -, -CH 2 -CH 2 -NH 50 -CH 2 -CH 2 -, or -CH 2 -NQ 50 -CH 2 -CH 2 -CH 2 -, where Q 50 represents H or C 1-4 alkyl optionally substituted with 1-3 of = O, or -OH. The compound of claim 12, wherein Q 50 represents methyl, isopropyl, ethyl, formyl, acetyl, or -C (O) -CH 2 OH. A compound of claim 2 of formula III or a pharmaceutically acceptable salt thereof wherein: A represents a structure i, ii, or iii ΡΕ1478629 9 ΡΕ1478629 l) a diazinyl group optionally substituted with X and Y, m) a triazinyl group optionally substituted with X and Y, n) a guinolinyl group optionally substituted with X and Y, o) a guinoxalinyl group optionally substituted with X and Y, p ) a naphthyridinyl group optionally substituted with X and Y ΡΕ1478629 10 ΡΕ1478629 11 ΡΕ1478629 12 13 ΡΕ1478629 B and an R2 are taken together to form 14 ΡΕ1478629 A1 represents a) H-, or b) CH3; (a) -NH-, -C (O) -NH-, g) -CH 2 -C (O) -NH-, (C 1 -C 3) -O-C (O) h) HO-CH 2 -, i) CH 3 -CH 2 - (0) -ch2-, m) 0 V-? , or 15 ΡΕ1478629 A1 and A2 taken together represent: é-f. b) 0 =, or c) N =; 5-10 par-A3 represents any aryl or het aromatic ring of members, the het 1-4 heteroatoms selected from O, S, or N; (B) -C (H) = NC (H) = C (H) Di represents a) 0, b) S, or c) -n (r304) -; E represents a) NR 39, b) -S (= O) i, c) 0, or d) -s (= O) (= nr 3i 5); F1 represents a) 0, b) S, 16 ΡΕ1478629 c) NH, d) N-OH, e) N-O-C1-4 alkyl, or f) N-OC (O) -C4-4 alkyl; Κι represents a) 0, b) S, or c) -NR305-; M represents a) H, b) C4-alkyl, c) C3-8 cycloalkyl, d) - (CH2) m OR13, or e) - (CH2) h -NR24R22; T i is a) -O-, b) -NR306- c) -S-, or d) -SO2-; V represents a) 0, b) CH2, or c) nr87; W represents a) CH, or b) N; W 1 represents a) -NH-, b) 0, or c) S; (A) - (a) - (b) - (O) - (R 2) halo, e) -no 2, f) tetrazoyl, g) -SH, h) -S (= O) (R 25) (R 25) (R 2), -OR 13, -C (= O) R 17, n) -C (R25) (R28) -OC (= O) R13, o) -C (R28) (O R13) - (CH2) h -NR27 R28, P) -NR27 R21, q) -N (R27) = O) R7, r) -N (R27) -S (= O) R7, s) -C (OR14) (OR15) R28 rt) -C (R25) (R16) -NR27 R26, or u) Substituted with one or more halos, OH, = 0 at a position other than the alpha position, -S (= O) R 1 ', -NR 27 R 28, C 2-5 alkenyl, C 2-5 alkynyl, or C 3-8 cycloalkyl; Y represents a) H, b) F, c) 1-1 d) Br 18 ΡΕ1478629 e) C1-3 alkyl, 1 f) NO2; ζ represents a) 0, b) S, or c) NM; Ζ represents (a) -CH 2 -, b) -CH (R 14) -CH 2 -, c) -C (O) or d) -CH 2 CH 2 CH 2 -; R 2 represents a) -S (O) b b) -O-, c) -N (R07) - R (d) -S (= O) (= NR315 Ζ3 represents a) -S (O) b) -O-, ζ4 is a) -S (= O) i-, or b) -NR303-; R 5 represents a) -O-, b) -NH-, c) -CH 2 -, or d) -s (= O) 1 -; ζ6 represents a) S (= O) if 19 ΡΕ1478629 b) S (= NR315), or c) S (= NR315) (= 0); a) N, b) CR110, c) CR115, or d) CR116; Z represents a) 0, or b) S; R1 represents a) H, b) -OH, c) C1-6 alkyl optionally substituted with one or more halo, -OH, -CN, aryl, het, alkoxy, substituted or substituted hetaryl, d) C1-6 alkoxy optionally substituted with one or more more halos, -OH, -CN, aryl, het, substituted aryl or het substituted, e) C1-6 alkoxy optionally substituted with aryl, het, substituted aryl or het substituted, f) -nh2, or g) C3-5 cycloalkyl; R2 represents a) H, b) C1-2 alkyl optionally substituted with one or more halos, c) -NH2, d) -NO2, 20 Ρ AND1478629 e) -CN, or f) halo; R4 represents a) C1-4 alkyl optionally substituted with one or more halos, OH, CN, NR10R11, or -C02R13a b) C2-4 alkenyl, c) -NR16R18, d) -NHC (= O) r7, e) -NR20C (= O) R7, f) -N (R17) 2, g) -NR16R17, or h) -NR17R2q, Rs and R6 at each occurrence are the same or different represent a) C1-2 alkyl, or b) R5 and R6 taken together represent - (CH2) k-; R7 represents a) C1-4 alkyl optionally substituted with one or more halos; Rio and Rn at each occurrence are different or different and represent a) H, b) C1-4 alkyl, or c) C3-8 cycloalkyl; R13 represents a) H, or b) C1-4 alkyl; R14 and R15 at each occurrence are the same or different and represent 21 ΡΕ1478629 a) C1-4 alkyl, or b) R14 and R15 taken together represent - (CH2) n -; R16 represents a) H, b) C1-4 alkyl, or c) C3-8 cycloalkyl; R17 represents a) C1-4 alkyl, or b) C3-8 cycloalkyl; R 1 represents a) H, b) C 1-4 alkyl, c) C 2-4 alkenyl, d) C 3-4 cycloalkyl, e) -OR 13 or f) -NR 21 R 22 / R 20 represents a pharmaceutically acceptable cation such as sodium, potassium, lithium, calcium or magnesium; R21 and R22 at each occurrence are the same or different and represent a) H, b) C1-4 alkyl, or c) R2 and R22 taken together represent - (CH2) m-; R25 represents a) H, b) C1-8 alkyl optionally substituted with one or more halos, C3-8 cycloalkyl, C1-4 alkyl substituted with one or more of -S (= O) R17, -OR13, or C (= O) R 3, NR 27 R 28, or c) C 2-5 alkenyl optionally substituted with -C (O) H, or CO 2 R 13; R 21 represents a) R 28, or b) -NR 27 N 28; R 27 and R 2g at each occurrence are the same or different and represent a) H, b) C 1-8 alkyl, c) C 3-8 cycloalkyl, d) - (CH 2) m OR R 13 taken in (CH 2) 2, - (CH 2) h CH (COR 7) -, or - (CH 2) 2 N (CH 2) 2 (R '); R 29 represents a) -NR 27 R 28, b) -OR 27, or c) -NHC (= O) r 28; R30 represents a) H, or b) C1-4 alkyl optionally substituted with one or more halos, OH, C1-4 alkoxy, CN, SH, NH2, -OR31, -NHR31, -N (R31) 2, or -S (O) (R 31); R31 represents a) C1-4 alkyl, b) -C (O) C1-4 alkyl, c) -C (O) O-C1-4 alkyl, d) -C (O) NH2, e) -C (O) NH- or -C? -C? alkyl; f) 23 ΡΕ1478629 R.38 represents a) H, b) C4-6 alkyl, c) - (CH2) q -aryl, or d) halo; R39 represents H, b) C1-6 alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH2) q -aryl, d) -CO2 R4o, e) -COR41, f) -C ( = 0) - (CH2) q C (= O) r40, g) -S (= O) 2-C1-6 alkyl, h) -S (= O) 2- (CH2) q -aryl, or D - ( C = O) j-Het; R 4a represents a) H, b) C 1-6 alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH 2) q -aryl, or d) - (CH 2) q -OR 42; R 4i represents a C 1-6 alkyl optionally substituted with one or more OH, halo, -O P (O) (OH) 2, -O P (OH) 2, or -CN, b) - (CH 2) q -aryl, or c) - (CH 2) q -O R 42; R42 represents a) b) C1-6 alkyl, c) - (CH2) q -aryl, or d) -C (= O) -C1-6 alkyl, R49 and R50 at each occurrence are the same or different and represent a) H, b) C1-4 alkyl, c) C5-6 cycloalkyl, or d) R49 and R50 taken together with the nitrogen atom represent a saturated 5-6 membered heterocyclic moiety having, optionally, an additional heteroatom selected from the group consisting of S, N, and O, and may be in turn optionally substituted with, on the additional nitrogen atom, C1-3 alkyl or C1-3 acyl; R 51 represents a) carboxyl, b) halo, c) 10 sd) mercapto, e) formyl, f) cf 3, g) -NO 2, h) C 1-6 alkoxy, i) C 1-6 alkoxycarbonyl, C 1-6 alkyl, optionally substituted with OH, C 1-5 alkoxy, C 1-5 acyl, or -NR 49 R 50, m) phenyl, n) -C (= O) NR 52 R 53 , o) -NR 49 R 50, P) -N (R 52) (-so 2 R 54), q) -SO 2 -NR 52 R 53, or r) -s (= O) R 54; R52 and R53 at each occurrence are a) H, b) C1-6 alkyl, or c) phenyl; R54 represents a) C1-4 alkyl, or b) phenyl optionally C1-4; R73 and R74 at each occurrence are a) H, b) carboxyl, c) halo, d) -CN, e) mercapto, f) formyl, g) cf3, h) j) C1-6 alkoxycarbonyl, k) C1-6 alkylthio, i) C1-6 acyl, same or different and substituted with identical or different alkyl and 26 ΡΕ1478629 m) -NR78R79, n) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, -NR78R79, -N (phenyl) (CH2-CH2-OH), -O-CH (CH3) (OCH2CH3), or -O-phenyl- [para-NHC (= O ) CH3], o) C2-s-phenyl alkenyl optionally substituted with R5i, p) phenyl optionally substituted with R5i, or q) a saturated or unsaturated, 5-6 membered heterocyclic moiety having one to three atoms selected from group consisting of S, N, and O, optionally substituted with R51; R 78 and R 79 at each occurrence are the same or different and represent a) H, b) C 1-4 alkyl, c) phenyl, or d) R 78 and R 79 taken together with the nitrogen atom represent a saturated 5-6 membered heterocyclic moiety which optionally has an additional heteroatom selected from the group consisting of S, N, and O, and may in turn be optionally substituted with, on the additional nitrogen atom, C1-3 alkyl or C1-3 acyl; R 2 represents a) H, b) formyl, c) carboxyl, d) C 1-6 alkoxycarbonyl, e) C 1-8 alkyl, f) C 2-8 alkenyl, 27 ΡΕ1478629 wherein the substituents (e) and (f) may be optionally substituted with OH, halo, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio or C1-6 alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF 3, -NO 2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 acyl, C 1-6 alkylthio, or C 1-6 alkoxycarbonyl; h) -NR8 R82, i) -OR90, j) -S (= O) iRgi, or k) -S02 -N (R92) (R93); R8i and R82 at each occurrence are the same or different and represent a) H, b) C3-6 cycloalkyl, c) phenyl, d) C1-6 acyl, e) C1-8 alkyl optionally substituted with OH, C1-6 alkoxy which may be substituted with OH, a 5-6 membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF 3, halo, -NO 2, C 1-4 alkoxy, -NR 83 R 84 , or f) or â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (28) and (21) in each occurrence are the same or different and represent a) H, or b) C1-4 alkyl; R 5 represents a) OH, b) C 1-4 alkoxy, or c) -NR 8g R 9; R86 represents a) H, or b) C1-7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazolyl, methylthio, amino, phenyl optionally substituted with OH, -C (= O) -NH2, -CO2H, or -C ( = NH) -NH 2; R7 represents a) H, b) phenyl, or c) C1-6 alkyl optionally substituted by OH; Rgg and Rg9 at each occurrence are the same or different and represent a) H, b) C 1-5 alkyl c) C 3-6 cycloalkyl, or d) phenyl; R 90 represents a) C 1-6 alkyl optionally substituted with C 1-6 alkoxy or C 1-6 hydroxy, C 3-6 cycloalkyl, an optionally benzo-condensed, 6-membered aromatic heterocyclic moiety having one to three nitrogen atoms, which may, be substituted with one or two -NO 2, CF 3, halo, -CN, OH, C 1-5 alkyl, C 1-5 alkoxy, or C 1-5 acyl; b) X- / c) phenyl, or d) pyridyl; R91 represents a) C1-6 alkyl, b) C2-16 alkenyl wherein the substituents (a) and (b) may be optionally substituted with C1-6 alkoxycarbonyl, or a 5-6 membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aryl having 6 to 10 carbon atoms, or d) a 5-6 membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (c) and (d) may be optionally substituted with carboxyl, halo, -CN, formyl, CF 3, -NO 2, C 1-6 alkyl, C 1-6 alkoxy C 1-6 acyl, C 1-6 alkylthio, or C 1-6 alkoxycarbonyl; R92 and R93 at each occurrence are the same or different and represent 30 ΡΕ1478629 a) H, b) phenyl, c) C1-6 alkyl, or d) benzyl; R 1 represents a) H-, b) ch 3 -, c) phenyl-CH 2 -, or d) CH 3 C (O) R 7 is a) (C 1 -C 3) alkyl-, or b) phenyl-; R104 represents a) H-, or b) R106 represents a) CH3-C (O) b) C H (O) c) CI2CH-C (O) d) HOCH2 -C (O) e) ) g. g) F2CHC (0) 31 ΡΕ1478629 l) C = CH-CH 2 -CH 2 -C (O) -, m) phenyl-CH 2 -O-CH 2 -C (O) -, o) C 1-4 alkyl-NH- C1-4 alkyl optionally substituted with one or more halo, CN, NO2, OH, SH, or NH2; R102-C (O) - (R111) -C (O) -, b) R103 O-C (O) -, c) R108 -C (O) -, O f) H 3 C-C (O) - (CH 2) 2 -C (O) -, g) R 109 -SO 2 - i) HO-CH2-C (O) -, j) R116 - (CH2) 2-, k) R113-C (O) -O- C (O) -NH-, ΡΕ), c) C 1 -C 4 alkyl, C 1 -C 4 alkyl, aryl- (CH2) n, d) CIH2C-, e) CI2HC-, f) fh2c-, g) f2hc-, h) (C3-C6) cycloalkyl, or i) cnch2-. R109 represents a) C1-C4 alkyl, b) -CH2 Cl c) -ch2ch = ch2, d) aryl, or e-CH2 CN; R110 and R111 are independently a) H-, b) CH3-; or R 12 represents a) H-, b) CH 3 O-CH 2 O-CH 2 -, or c) HOCH 2 -; R113 represents a) ch3 -, b) HOCH2 -, c) (CH3) 2 N -phenyl, or 33 ΡΕ1478629 d) (CH3) 2 N-CH2 -; R114 represents a) HO-, b) CH3 O-, c) H2N-, d) CH30 -C (O) -0, e) CH3 -C (O) -O-CH2 -C (O) -O-, f ) -CH 2 -O-CH 2 -O-CH 2 -O- (CH 2) 2 -O-, or i) CH 3 - CH2 -O-; R115 represents a) H-, or b) Cl-; R116 is a) HO-b) CH30-, or c) F; R150 and R151 are each independently a) H, b) C1-C4 alkyl, or c) R150 and R151 taken together with the nitrogen atom to which R150 and R151 are attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms; Each R3ocn R3oir R302? R303? R3oo R3os? R R306 is independently selected from a) H, b) C3-6 cycloalkyl optionally substituted with ΡΕ1478629 34 = 0, c) C1-6 alkoxy, d) C1-6 alkyl optionally substituted with or more than R310, e) optionally substituted C2-10 alkenyl substituted or unsubstituted or substituted by one or more of R310, f) benzyloxycarbonyl, g) aryl, h) het, i) -C (O) -NR311R312, j) -S (O) 2 -NR3 R3i2, k) (O) -R310, m) -C (S) -NR311R312, n) -C (O) -H, or o) -C (O) -C1-4 alkyl optionally substituted one or more of R310; R310 represents a) -CN, b) -N3, c) -CF3, d) pyridyl, e) halo, f) -OH, g) -O (O) C1-C6 alkyl, h) oxycarbonyl, D-SH, j) -NH 2; (A), b) C1-4 alkyl, c) phenyl, or d) R311 and R312 together with the N atom to which they are attached form a ring 5- or 6-membered saturated heterocyclic group optionally having one or more O, S, or N atoms in the ring, the heterocyclic ring being optionally substituted with C 1-3 alkyl; R315 represents a) H, b) C1-4 alkyl optionally substituted with halo, -OH, C1-8 alkoxy, amino, C1-8 alkylamino, or di-C1 -C6 -alkylamino, c) aryl-S (O) 2- , d) C (= O) C1-4 alkyl, e) C (= O) O-C1-4 alkyl, f) C (= O) NHR320, g) C1-4 alkyl, i) -S (O) -C1-4 alkyl, j) C1-4 alkyl-C1-4 alkyl, or k) C1-4 alkyl-C1-4 alkyl; R 32o is independently selected from a) H, or b) substituted alkyl; Each R325, R326, R327r and R328 is independently selected from a) H, b) C1 -C6 alkyl, c) substituted alkyl, d) halo, or e) R325 and R326 or R327 and R3; or = S, or one of R325 or R326 -N (R303) -i together with those, they are attached form members containing one or more of O, S, or N; R330 represents a) H, or b) alkyl, or c) substituted alkyl; R331 represents a) R332 b) I) c) n h2, d) OH, e) NHC1 -C4 alkyl, or f) R315; R332 represents a) H, b) C1-C4 alkyl, c) 0-C1-C4 alkyl, d) S-C1-C4 alkyl, or e) NH-C1-4 alkyl R333 represents a) F, or b) R332 ; R5oo and R503 are each independently selected from the group consisting of (a) H, (b) halo, (c) C1 -C8 alkyl, (d) C3 -C6 cycloalkyl, (e) - (CH2) i-OR511, or f) -C (= O) -R 541; R 5a and R 502 each represent, independently (a) hydrogen atom, (b) C 1 -C 8 alkyl, (c) C 1 -C 8 alkoxy, (d) C 1 -C 8 alkylthio, (e) - (G) -NR 53 R 552 t (h) -C (= O) -NR 5 42 R 552 (i) - (CH 2) i C (= O) -R 54 i , or R 501 and R 502 together form (j) = 0, (k) = NR 543, (D = S, (m) = CR 5 44 R 554, OR (n) a 5- or 6-membered saturated or unsaturated hetero ring having 1 -3-heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; R511 and R512 each represent, independently, (a) hydrogen atom, (b) C1 -C6 alkyl (B) - (CH2) m -OH, (c) C1 -C6 alkyl, (d) C1 -C6 alkoxy or (e) -O-CH2 O-C (= O) -R5II, R542 and R552 each independently represent (a) hydrogen atom, (c) C1 -C6 alkyl, (d) -C (= 0) -R541 (e) -C (= O) -NR544 R522, (f) - (CH2) q enyl or or R 542 and R 552 together form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, or a thiomorpholino group, each of which may be substituted by C 1 -C 6 alkyl or - (CH 2) -OH; R543 represents (a) H, (b) -OR551, (c) C1 -C8 alkyl, (d) C1 -C8 alkoxy, (e) - (CH2) q -phenyl, (f) -NR542 R5521 (g) -NH -C (= NH) -NH 2, or (h) [1,2,4] triazol-4-yl; R544 and R554 each represent, independently, a) H, (b) C1 -C6 alkyl, (c) -C (= O) -R541 r or 39 ΡΕ1478629 (d) - (CH2) q -phenyl; R55 represents (a) H, (b) C1 -C6 alkyl, (c) C1 -C6 alkyl substituted with 1-3 halo, (d) - (CH2) t-OR5 iii, (e) - (CH2) (= O) -R54i, or (f) -C (= o) - (CH2) m-OR544; R600 represents a) H, b) C1-C4 alkyl c) het, d) (CH2) bC (O) O-C1-C4 alkyl, e) (CH2) bC (O) C1-C4 alkyl, or f) aryl ; R601 and R602 each independently represent a) H, b) C1 -C4 alkyl, c) het, d) C3 -C6 cycloalkyl, e) aryl, f) O-C1 -C4 alkyl, g) ) O-C 1 -C 4 alkyl or h) R 60 i and R 602 taken together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; Each R700 / R701 / R702 / R703 / R704 / and R705 is independently selected from a) H40 ΡΕ1478629 b) C1-4 alkyl optionally substituted with 1-3 = 0, = -OH, -C (f) substituted aryl, (g) het, h) and het substituted, i) 0, 0) C1-4 alkyl, or (k) R700 and R701 form = O or = S, or D R702 and R703 form = O or = S, or m) R704 and R705 form = O or = S; a is 1 or 2; b is 0 or 1; h represents 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; 1 is 1 or 3; m is 1, 3, 4 or 5; n is 0, 1, 2, 3, 4, or 5; P represents 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are 1, 2, 3,4, or 5; q is 1, 2, 3, or 4; t is 0, 1, 2, 3, 4, 5, or 6; and w represents 0, 1, 2, or 3. The compound of claim 14, wherein each R 2 is independently selected from H, F, Cl, CH 2, CH 2 CN, NH 2, NO 2, CF 3, and CH 3. The compound of claim 14, wherein the structure of A is O. 17. The compound of claim 14, wherein R2 represents H, -NH2, -OH, C1-4 alkyl, C3-5 cycloalkyl, C1-4 alkoxy, or alkenyl The alkyl and alkoxy being each substituted with one or more halo, -OH, -CN. The compound of claim 17, wherein R 2 is H -OH, -CH 2 -CH = CH 2, methyl, ethyl, propyl, -CH 2 -CH 2 F, -CH 2 -CH 2 OH, or methoxy. The compound of claim 14, wherein B is selected from ΡΕ1478629 42 The compound of claim 14, wherein B represents X. (C The compound of claim 14, wherein B ΡΕ 14777293 represents 22. represents the compound of claim 14, wherein B% SI &gt; = R332. represents the compound of claim 14, wherein B 24. represents the compound of claim 14, wherein B The compound of claim 14, wherein B represents ΡΕ1478629 The compound of claim 14, wherein B represents The compound of claim 14, wherein B represents The compound of claim 14, wherein B and a R 2 form 32B r325 r327. 2 ^ Z5 'Rm * or 45 ΡΕ1478629 The compound of claim 28, wherein B and a R 2 form -C (O) -N (R 300) -O-C (O) -N (R 300) -N (R 10 6) -HCR 30 -CH 2 -, -NR 300 -C (O) -C (R 327R328) -O-, -NR300 -C (O) -C (R327R328) -S-, -nr300-c (S) -c (r327R328) -s-, -nr300-c (O) -c (r327R328) -CH2-, -CH2-CH2-NR107-CH2-CH2-, or -CH2 -NR107 -CH2 -CH2 -CH2 -. The compound of claim 28, wherein B and a R 2 form R300 The compound of claim 30, wherein Di is S or 0. 32. The compound of claim 30, wherein R 300 represents C 1-4 alkyl. The compound of claim 32, wherein R 30 'is methyl, ethyl, or isopropyl. The compound of claim 28, wherein B and a R2 form 46 ΡΕ1478629 The compound of claim 28, wherein R 2, The compound of claim 28, wherein R2 is , wherein B and 37. The compound of claim 28 and R2 form The compound of claim 14, is hydrogen and the other R 2 is: The compound of claim 14, the substituents R 2 represent F. A compound of claim 1 wherein an R 2 wherein both is selected from (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-methyl-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-allyl-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-propyl-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-methoxy-2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- [3,5-difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3-Fluoro-4- (4-morpholinyl) phenyl] -N-hydroxy-2-oxo-5-oxazolidinecarboxamide; and (5R) - (-) - 3- [3,5-Difluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide. 41. A compound of claim 1 selected from (5R) - (-) - 3- [4- (3-Pyridyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; and (5R) - (-) - 3- [4- (4-Pyridyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) - (-) - 3- [4- (3,6-Dihydro-2 H -pyran-4-yl) -3-fluorophenyl] -2-oxo -5-oxazolidinecarboxamide; and 48 ΡΕ1478629 (5R) - (-) - 3- [4- (Tetrahydro-2 H -pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) -3- [4- (3,6-dihydro-2 H -pyrazan-4-yl) -3-fluorophenyl] -2- oxo-5-oxazolidinecarboxamide; 5.5 (5R) - (-) - 3- [4- (3,6-dihydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5 (5R) - (-) - 3- [4- (tetrahydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (cis -tetrahydro-1-oxido-2-fluoro-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (trans -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5 (5R) - (-) - 3- [4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (cis -tetrahydro-1-oxido-2 H -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (trans-tetrazol-2-yl) -thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) - (-) - N-methyl-3- [4- (tetrahydro-2H-thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5 (5R) -3- [3,5-Difluoro-4- (tetrahydro-2H-thio-pyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide dioxide; (5R) - (-) - 3- [3,5-Difluoro-4- (e -tetrahydro-1-oxido-2-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- [3,5-Difluoro-4- (trans-tetrazol-2-ylthiopyran-4-yl) phenyl] -2-oxo-5- oxazolidinecarboxamide; 49 ΡΕ1478629 (5R) -N-Methyl-3- [3,5-difluoro-4- (trans -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide ; (5R) -3- [4- (cis-1- (methylimino) -1-oxido-1,3,3,4,5,6-hexahydro-2H-pyrazan-4-yl) -3- fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (cis-1-imino-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3 -fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (cyclohexyl-1-oxido-1,1,3,4,5,6-hexahydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (cis-1- (methylimino) -1-oxido-1,3,3,4,5,6-hexahydro-2 H -pyranan-4-yl ) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (trans-1- (imino) -1-oxido-1,3,3,4,5,6-hexahydro-2H-thiopyran-4-yl) -3-fluorophenyl] ] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (trans-1- (imino) -1-oxido-1,3,3,4,5,6-hexahydro-2 H -pyranan-4-yl ) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (trans-1- (methylimino) -1-oxido-1,3,3,4,5,6-hexahydro-2 H -pyrazan-4-yl) -3- fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (trans-1- (methylimino) -1-oxido-1,1,3,4,5,6-hexahydro-2 H -thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; 5.5- (5R) -3- [4- (3,6-Dihydro-2 H -thiopyran-4-yl) -3,5-difluorophenyl] -N-methyl-2-oxo-5-oxazolidinecarboxamide; 50 ΔΕ1478629 5.5 (5R) -3- [4- (3,6-Dihydro-2H-thiopyran-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide dioxide; and (5R) -N-Methyl-3- [3-fluoro-4- (trans -tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 which is (5R) - (-) - 3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) - (-) - 3- [4- (thiomorpholin-4-yl) -3,5-difluorophenyl] -2-oxo-5- oxazolidinecarboxamide; 5.5- (5R) - (-) - 3- [4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide dioxide; 5.5- (5R) - (-) - 3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide dioxide; (5R) - (-) - 3- [3-fluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide; (5R) -3- [3-Fluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3-Fluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3-Fluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3,5-Difluoro-4- (1-imino-1-oxido-4-thiomorphorophenyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3,5-Difluoro-4- (1-imino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3,5-Difluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3,5-Difluoro-4- (1-methylimino-1-oxido-4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5 R) - (-) - 3- [3,5-Difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide; (5 R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S-oxide; and (5R) - (-) - N-methyl-3- [3,5-difluoro-4- (thiomorpholin-4-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide S, S-dioxide. A compound of claim 1 selected from (5R) - (-) - 3- (2,3-Dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide ; (5R) - (-) - 3- (2,3-Dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- (2,3-Dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Ethyl-3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N- (2-Hydroxyethyl) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (2R) -Î ± - (2-Fluoroethyl) -3- (2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide; and (5R) -N-Methyl-3- (2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl) -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) - (-) - 3- (2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide ; (5R) - (-) - 3- (2,3-Dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - 3- (2,3-Dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; 53 ΡΕ1478629 (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) - (-) - N-Methyl-3- (2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzoxazol-2-yl) -5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,3-Dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide; and (5R) -N-Methyl-3- (2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzoxazolyl) -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) -3 - [(2R) -2,3-Dihydro-1-formyl-2-methyl-1 H -indol-5-yl] -2-oxo -5-oxazolidinecarboxamide; (5R) -3 - [(2R) -2,3-Dihydro-1- (hydroxyacetyl) -2-methyl-1 H -indol-5-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (5,7-Dihydro-6 H -pyrrolo [3,4-b] pyridin-6-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; and (5R) -N-methyl-3- [4- (5,7-dihydro-6 H -pyrrolo [3,4- b] pyridin-6-yl) -3-fluorophenyl] -2-oxo-5- oxazolidinecarboxamide. 54 ΡΕ1478629 A compound of claim 1 selected from (5R) - (-) - 3- [3,5-Difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl) phenyl] -2- oxo-5-oxazolidinecarboxamide; (5R) -3- [3,5-Difluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3,5-difluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3-Fluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [3-fluoro-4- (1-formyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide; and (5R) - (-) - N-Methyl-3- [3,5-difluoro-4- (1-methoxycarbonyl-3-methylazetidin-3-yl) phenyl] -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) -3- (3,4-Dihydro-4-methyl-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo -5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3,4-dihydro-4-methyl-3-oxo-2-yl) -1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N- (2-Fluoroethyl) -3- (3,4-dihydro-4-methyl-3-oxo-2 H -1,4-benzoxazin-7-yl) -2- 5-oxazolidinecarboxamide; (5R) -3- (3,4-Dihydro-4-methyl-3-oxo-2-yl) -1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-5β, 14-yl) -6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (2,2-Difluoro-4-methyl-3,4-dihydro-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide ; (5R) -N-Methyl-3- (2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2,7-benzoxazin-7-yl) -2-oxo-5- oxazolidinecarboxamide; (5R) -3- (8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (4-Methyl-3-thioxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2,7-1,4-benzothiazin-7-yl) -2-oxo-5-oxazolidinecarboxamide ; (5R) -N-Methyl-3- (3,4-dihydro-5-fluoro-4-methyl-3-oxo-2 H -1,4-benzothiazin-7-yl) -2-oxo-5- oxazolidinecarboxamide; (5R) -3- (3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2 H -1,4-benzoxazin-7-yl) -2-oxo-5-oxazolidinecarboxamide ; and (5R) -N-Methyl-3- (3,4-dihydro-5-fluoro-4-methyl-3-oxo-2,1-benzoxazin-7-yl) -2- 5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) -3- [3-Fluoro-4- (5-oxo-5,6-dihydro-4H- [1,3,4] thiadiazin-2-yl ) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (1,1-Dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; and 56 ΡΕ1478629 (5R) -3- [4- (2,5-Dihydro-1 H -pyrrol-1-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluoro-phenyl] -2- oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N- (2-Fluoroethyl) -3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (4-Oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Ethyl-3- [4- (4-oxo-3,4-dihydro-1 (2H) -pyridinyl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; and (5R) -3- [4- [3,4-Dihydro-4- (hydroxyimino) -1 (2H) -pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide. 57 ΡΕ1478629 A compound of claim 1 selected from (5R) -3- (2-Formyl-2,3,4,5-tetrahydro-1-2-benzazepin-7-yl) -2-oxo-5- oxazolidinecarboxamide; (5R) -N-Methyl-3- (2-formyl-2,3,4,5-tetrahydro-1-2-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [2- (Hydroxyacetyl) -2,3,4,5-tetrahydro-1-2-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [2- (hydroxyacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- (3-Formyl-2,3,4,5-tetrahydro-3-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- (3-formyl-2,3,4,5-tetrahydro-17-benzazepin-7-yl) -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [3- (Hydroxyacetyl) -2,3,4,5-tetrahydro-3-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide; and (5R) -N-Methyl-3- [3- (hydroxyacetyl) -2,3,4,5-tetrahydro-3-benzazepin-7-yl] -2-oxo-5-oxazolidinecarboxamide. A compound of claim 1 selected from (5R) -3- [4- (1- (2 (S) -Hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4- yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -N-Methyl-3- [4- (1- (2 (S) -hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5- difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (1- (2 (S), 3-Dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl] -2-oxo-5-oxazolidine-carboxamide; (5R) -N-Methyl-3- [4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5- difluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (1- (2 (S) -Hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] -2-oxo -5-oxazolidine-carboxamide; (5R) -N-Methyl-3- [4- (1- (2 (S) -hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidinecarboxamide; (5R) -3- [4- (1- (2 (S), 3-Dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl] -2-oxo -5-oxazolidinecarboxamide; and (5R) -N-Methyl-3- [4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl ] -2-oxo-5-oxazolidine-carboxamide. The use of a compound of claim 1 or claim 14 in the manufacture of a medicament for the treatment of bacterial infections in mammals. A pharmaceutical composition comprising a compound of claim 1 or a compound of claim 14 and a pharmaceutically acceptable carrier. ΡΕ1478629 59 Lisbon, November 23, 2006